EP2336161A2 - Oligomères de beta(1-42 amyloïdes, dérivés de ceux-ci et anticorps destinés à ceux-ci, procédé de fabrication et utilisation de ces composés - Google Patents
Oligomères de beta(1-42 amyloïdes, dérivés de ceux-ci et anticorps destinés à ceux-ci, procédé de fabrication et utilisation de ces composés Download PDFInfo
- Publication number
- EP2336161A2 EP2336161A2 EP10179281A EP10179281A EP2336161A2 EP 2336161 A2 EP2336161 A2 EP 2336161A2 EP 10179281 A EP10179281 A EP 10179281A EP 10179281 A EP10179281 A EP 10179281A EP 2336161 A2 EP2336161 A2 EP 2336161A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- protein
- oligomer
- amyloid
- oligomers
- antibody
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 108010064539 amyloid beta-protein (1-42) Proteins 0.000 title claims abstract description 75
- 238000004519 manufacturing process Methods 0.000 title claims description 35
- 238000000034 method Methods 0.000 claims abstract description 142
- 239000000203 mixture Substances 0.000 claims abstract description 94
- 238000001727 in vivo Methods 0.000 claims abstract description 42
- 239000003599 detergent Substances 0.000 claims abstract description 27
- 238000001502 gel electrophoresis Methods 0.000 claims abstract description 16
- 108090000623 proteins and genes Proteins 0.000 claims description 209
- 102000004169 proteins and genes Human genes 0.000 claims description 164
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 51
- 238000000338 in vitro Methods 0.000 claims description 38
- 108010090849 Amyloid beta-Peptides Proteins 0.000 claims description 37
- 102000013455 Amyloid beta-Peptides Human genes 0.000 claims description 37
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 29
- 201000010099 disease Diseases 0.000 claims description 26
- 230000008569 process Effects 0.000 claims description 25
- 238000001514 detection method Methods 0.000 claims description 14
- 238000011282 treatment Methods 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 11
- 208000024827 Alzheimer disease Diseases 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 229960005486 vaccine Drugs 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 230000002378 acidificating effect Effects 0.000 claims description 3
- 125000003342 alkenyl group Chemical group 0.000 claims description 3
- 239000000126 substance Substances 0.000 abstract description 59
- 230000027455 binding Effects 0.000 abstract description 58
- 230000003053 immunization Effects 0.000 abstract description 54
- 230000000694 effects Effects 0.000 abstract description 32
- 210000002569 neuron Anatomy 0.000 abstract description 16
- 238000012360 testing method Methods 0.000 abstract description 11
- 239000003446 ligand Substances 0.000 abstract description 9
- 206010029260 Neuroblastoma Diseases 0.000 abstract description 6
- 239000011734 sodium Substances 0.000 abstract description 6
- 230000006907 apoptotic process Effects 0.000 abstract description 2
- 238000010304 firing Methods 0.000 abstract description 2
- 230000004083 survival effect Effects 0.000 abstract description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 abstract 1
- 230000001939 inductive effect Effects 0.000 abstract 1
- 230000010534 mechanism of action Effects 0.000 abstract 1
- 230000000324 neuroprotective effect Effects 0.000 abstract 1
- 230000001777 nootropic effect Effects 0.000 abstract 1
- 229910052708 sodium Inorganic materials 0.000 abstract 1
- 235000018102 proteins Nutrition 0.000 description 145
- 238000002360 preparation method Methods 0.000 description 142
- 241000282414 Homo sapiens Species 0.000 description 118
- 239000000427 antigen Substances 0.000 description 111
- 108091007433 antigens Proteins 0.000 description 111
- 102000036639 antigens Human genes 0.000 description 111
- 210000004027 cell Anatomy 0.000 description 109
- 239000000243 solution Substances 0.000 description 66
- 241000700159 Rattus Species 0.000 description 54
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 50
- 239000012634 fragment Substances 0.000 description 49
- 239000000872 buffer Substances 0.000 description 46
- 210000002966 serum Anatomy 0.000 description 45
- 241001465754 Metazoa Species 0.000 description 42
- 238000002649 immunization Methods 0.000 description 39
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical class N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 32
- 241000283973 Oryctolagus cuniculus Species 0.000 description 32
- 239000002953 phosphate buffered saline Substances 0.000 description 30
- 241000699666 Mus <mouse, genus> Species 0.000 description 29
- 210000004408 hybridoma Anatomy 0.000 description 27
- 210000004698 lymphocyte Anatomy 0.000 description 26
- 238000012216 screening Methods 0.000 description 26
- 239000011780 sodium chloride Substances 0.000 description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 26
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 25
- 108020004414 DNA Proteins 0.000 description 24
- 235000001014 amino acid Nutrition 0.000 description 23
- 108060003951 Immunoglobulin Proteins 0.000 description 21
- 238000013459 approach Methods 0.000 description 21
- 102000018358 immunoglobulin Human genes 0.000 description 21
- 108090000765 processed proteins & peptides Proteins 0.000 description 21
- 229940024606 amino acid Drugs 0.000 description 19
- 239000013604 expression vector Substances 0.000 description 19
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 18
- 239000006228 supernatant Substances 0.000 description 18
- 150000001413 amino acids Chemical class 0.000 description 17
- 210000004369 blood Anatomy 0.000 description 17
- 239000008280 blood Substances 0.000 description 17
- 229960000587 glutaral Drugs 0.000 description 17
- 229960002685 biotin Drugs 0.000 description 16
- 235000020958 biotin Nutrition 0.000 description 16
- 239000011616 biotin Substances 0.000 description 16
- 210000004556 brain Anatomy 0.000 description 16
- 238000003018 immunoassay Methods 0.000 description 16
- 239000000523 sample Substances 0.000 description 16
- 239000000725 suspension Substances 0.000 description 16
- 210000004602 germ cell Anatomy 0.000 description 15
- 239000000178 monomer Substances 0.000 description 15
- 101710137189 Amyloid-beta A4 protein Proteins 0.000 description 14
- 102100022704 Amyloid-beta precursor protein Human genes 0.000 description 14
- 101710151993 Amyloid-beta precursor protein Proteins 0.000 description 14
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 14
- 239000004365 Protease Substances 0.000 description 14
- 125000003275 alpha amino acid group Chemical group 0.000 description 14
- DZHSAHHDTRWUTF-SIQRNXPUSA-N amyloid-beta polypeptide 42 Chemical compound C([C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O)[C@@H](C)CC)C(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C(C)C)C1=CC=CC=C1 DZHSAHHDTRWUTF-SIQRNXPUSA-N 0.000 description 14
- 239000003814 drug Substances 0.000 description 14
- 241000699670 Mus sp. Species 0.000 description 13
- 238000005516 engineering process Methods 0.000 description 13
- 230000014509 gene expression Effects 0.000 description 13
- 230000002163 immunogen Effects 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 239000002671 adjuvant Substances 0.000 description 12
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 12
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 12
- 238000011534 incubation Methods 0.000 description 12
- 229910000162 sodium phosphate Inorganic materials 0.000 description 12
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 12
- 239000013598 vector Substances 0.000 description 12
- 108020003175 receptors Proteins 0.000 description 11
- 102000005962 receptors Human genes 0.000 description 11
- 238000003259 recombinant expression Methods 0.000 description 11
- 239000001488 sodium phosphate Substances 0.000 description 11
- 230000001225 therapeutic effect Effects 0.000 description 11
- BYEAHWXPCBROCE-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropan-2-ol Chemical compound FC(F)(F)C(O)C(F)(F)F BYEAHWXPCBROCE-UHFFFAOYSA-N 0.000 description 10
- 230000009471 action Effects 0.000 description 10
- 239000000470 constituent Substances 0.000 description 10
- 238000005227 gel permeation chromatography Methods 0.000 description 10
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 9
- 229910019142 PO4 Inorganic materials 0.000 description 9
- 102000035195 Peptidases Human genes 0.000 description 9
- 108091005804 Peptidases Proteins 0.000 description 9
- 206010035226 Plasma cell myeloma Diseases 0.000 description 9
- 108090001109 Thermolysin Proteins 0.000 description 9
- 239000012141 concentrate Substances 0.000 description 9
- 239000002609 medium Substances 0.000 description 9
- 201000000050 myeloid neoplasm Diseases 0.000 description 9
- 238000006384 oligomerization reaction Methods 0.000 description 9
- 239000010452 phosphate Substances 0.000 description 9
- 230000001105 regulatory effect Effects 0.000 description 9
- 229920002994 synthetic fiber Polymers 0.000 description 9
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 8
- 206010012289 Dementia Diseases 0.000 description 8
- 208000032843 Hemorrhage Diseases 0.000 description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 8
- 235000008504 concentrate Nutrition 0.000 description 8
- 239000001963 growth medium Substances 0.000 description 8
- 230000035772 mutation Effects 0.000 description 8
- 230000003227 neuromodulating effect Effects 0.000 description 8
- 102000004196 processed proteins & peptides Human genes 0.000 description 8
- 230000009261 transgenic effect Effects 0.000 description 8
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 7
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 7
- 241000283707 Capra Species 0.000 description 7
- 102000004190 Enzymes Human genes 0.000 description 7
- 108090000790 Enzymes Proteins 0.000 description 7
- 241000287828 Gallus gallus Species 0.000 description 7
- -1 N-γ- maleimidobutyloxysuccinimide ester Chemical class 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 230000000740 bleeding effect Effects 0.000 description 7
- 238000004113 cell culture Methods 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 235000013330 chicken meat Nutrition 0.000 description 7
- 229940088598 enzyme Drugs 0.000 description 7
- 230000004927 fusion Effects 0.000 description 7
- 239000000499 gel Substances 0.000 description 7
- 239000003550 marker Substances 0.000 description 7
- 239000003147 molecular marker Substances 0.000 description 7
- 230000002441 reversible effect Effects 0.000 description 7
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 6
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 6
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 206010010099 Combined immunodeficiency Diseases 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 108700005091 Immunoglobulin Genes Proteins 0.000 description 6
- 239000005639 Lauric acid Substances 0.000 description 6
- 239000005642 Oleic acid Substances 0.000 description 6
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 6
- 108010076504 Protein Sorting Signals Proteins 0.000 description 6
- 230000009824 affinity maturation Effects 0.000 description 6
- 238000003556 assay Methods 0.000 description 6
- 238000010790 dilution Methods 0.000 description 6
- 239000012895 dilution Substances 0.000 description 6
- 238000011156 evaluation Methods 0.000 description 6
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 6
- 235000004554 glutamine Nutrition 0.000 description 6
- 230000028993 immune response Effects 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 6
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 6
- 229920001184 polypeptide Polymers 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 239000000700 radioactive tracer Substances 0.000 description 6
- 108700004121 sarkosyl Proteins 0.000 description 6
- 239000011550 stock solution Substances 0.000 description 6
- 239000000758 substrate Substances 0.000 description 6
- 238000001262 western blot Methods 0.000 description 6
- BHKKSKOHRFHHIN-MRVPVSSYSA-N 1-[[2-[(1R)-1-aminoethyl]-4-chlorophenyl]methyl]-2-sulfanylidene-5H-pyrrolo[3,2-d]pyrimidin-4-one Chemical compound N[C@H](C)C1=C(CN2C(NC(C3=C2C=CN3)=O)=S)C=CC(=C1)Cl BHKKSKOHRFHHIN-MRVPVSSYSA-N 0.000 description 5
- QRXMUCSWCMTJGU-UHFFFAOYSA-N 5-bromo-4-chloro-3-indolyl phosphate Chemical compound C1=C(Br)C(Cl)=C2C(OP(O)(=O)O)=CNC2=C1 QRXMUCSWCMTJGU-UHFFFAOYSA-N 0.000 description 5
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 5
- 102100034004 Gamma-adducin Human genes 0.000 description 5
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 5
- 101000799011 Homo sapiens Gamma-adducin Proteins 0.000 description 5
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 description 5
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 description 5
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 5
- 206010029350 Neurotoxicity Diseases 0.000 description 5
- 108090000526 Papain Proteins 0.000 description 5
- 206010044221 Toxic encephalopathy Diseases 0.000 description 5
- 108090000631 Trypsin Proteins 0.000 description 5
- 102000004142 Trypsin Human genes 0.000 description 5
- 230000002776 aggregation Effects 0.000 description 5
- 238000004220 aggregation Methods 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 229940098773 bovine serum albumin Drugs 0.000 description 5
- 210000003850 cellular structure Anatomy 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 238000004132 cross linking Methods 0.000 description 5
- 230000037029 cross reaction Effects 0.000 description 5
- 238000000502 dialysis Methods 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- 239000003623 enhancer Substances 0.000 description 5
- 230000036541 health Effects 0.000 description 5
- 210000004295 hippocampal neuron Anatomy 0.000 description 5
- 230000001900 immune effect Effects 0.000 description 5
- 108020004999 messenger RNA Proteins 0.000 description 5
- 238000001426 native polyacrylamide gel electrophoresis Methods 0.000 description 5
- 231100000228 neurotoxicity Toxicity 0.000 description 5
- 230000007135 neurotoxicity Effects 0.000 description 5
- 229940055729 papain Drugs 0.000 description 5
- 235000019834 papain Nutrition 0.000 description 5
- 238000002823 phage display Methods 0.000 description 5
- 210000002381 plasma Anatomy 0.000 description 5
- 235000019419 proteases Nutrition 0.000 description 5
- 241000894007 species Species 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 239000012588 trypsin Substances 0.000 description 5
- AXAVXPMQTGXXJZ-UHFFFAOYSA-N 2-aminoacetic acid;2-amino-2-(hydroxymethyl)propane-1,3-diol Chemical compound NCC(O)=O.OCC(N)(CO)CO AXAVXPMQTGXXJZ-UHFFFAOYSA-N 0.000 description 4
- 108090000317 Chymotrypsin Proteins 0.000 description 4
- 108020004635 Complementary DNA Proteins 0.000 description 4
- 241000701022 Cytomegalovirus Species 0.000 description 4
- 201000010374 Down Syndrome Diseases 0.000 description 4
- 238000002965 ELISA Methods 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 239000004471 Glycine Substances 0.000 description 4
- 102000003855 L-lactate dehydrogenase Human genes 0.000 description 4
- 108700023483 L-lactate dehydrogenases Proteins 0.000 description 4
- BACYUWVYYTXETD-UHFFFAOYSA-N N-Lauroylsarcosine Chemical group CCCCCCCCCCCC(=O)N(C)CC(O)=O BACYUWVYYTXETD-UHFFFAOYSA-N 0.000 description 4
- 108010067372 Pancreatic elastase Proteins 0.000 description 4
- 102000016387 Pancreatic elastase Human genes 0.000 description 4
- 108020004511 Recombinant DNA Proteins 0.000 description 4
- 108010090804 Streptavidin Chemical class 0.000 description 4
- 108091008874 T cell receptors Proteins 0.000 description 4
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 4
- 230000001580 bacterial effect Effects 0.000 description 4
- 230000006399 behavior Effects 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 238000005119 centrifugation Methods 0.000 description 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- 229960002376 chymotrypsin Drugs 0.000 description 4
- 230000000295 complement effect Effects 0.000 description 4
- 239000003431 cross linking reagent Substances 0.000 description 4
- 239000012228 culture supernatant Substances 0.000 description 4
- 238000001212 derivatisation Methods 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- 239000008103 glucose Substances 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 210000004962 mammalian cell Anatomy 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 238000002703 mutagenesis Methods 0.000 description 4
- 231100000350 mutagenesis Toxicity 0.000 description 4
- 230000003472 neutralizing effect Effects 0.000 description 4
- 229920000136 polysorbate Polymers 0.000 description 4
- 239000013641 positive control Substances 0.000 description 4
- 230000017854 proteolysis Effects 0.000 description 4
- 230000006337 proteolytic cleavage Effects 0.000 description 4
- 238000010186 staining Methods 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- 239000004094 surface-active agent Substances 0.000 description 4
- 229940124597 therapeutic agent Drugs 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 238000010626 work up procedure Methods 0.000 description 4
- 210000005253 yeast cell Anatomy 0.000 description 4
- AZUYLZMQTIKGSC-UHFFFAOYSA-N 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one Chemical compound ClC=1C(=C2C=NNC2=CC=1C)C=1C(=NN(C=1C)C1CC2(CN(C2)C(C=C)=O)C1)C=1C=C2C=NN(C2=CC=1)C AZUYLZMQTIKGSC-UHFFFAOYSA-N 0.000 description 3
- 208000037259 Amyloid Plaque Diseases 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 101000690301 Homo sapiens Aldo-keto reductase family 1 member C4 Proteins 0.000 description 3
- 101001116548 Homo sapiens Protein CBFA2T1 Proteins 0.000 description 3
- 102000004877 Insulin Human genes 0.000 description 3
- 108090001061 Insulin Proteins 0.000 description 3
- 229930195714 L-glutamate Natural products 0.000 description 3
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 3
- 241000829100 Macaca mulatta polyomavirus 1 Species 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 241001529936 Murinae Species 0.000 description 3
- 241001494479 Pecora Species 0.000 description 3
- 238000011579 SCID mouse model Methods 0.000 description 3
- 206010043376 Tetanus Diseases 0.000 description 3
- 108700019146 Transgenes Proteins 0.000 description 3
- 206010044688 Trisomy 21 Diseases 0.000 description 3
- 229920004890 Triton X-100 Polymers 0.000 description 3
- 230000001270 agonistic effect Effects 0.000 description 3
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 3
- 238000010171 animal model Methods 0.000 description 3
- 210000000628 antibody-producing cell Anatomy 0.000 description 3
- 230000000890 antigenic effect Effects 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 210000002798 bone marrow cell Anatomy 0.000 description 3
- 210000004958 brain cell Anatomy 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 230000001413 cellular effect Effects 0.000 description 3
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 3
- 238000003776 cleavage reaction Methods 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 210000003618 cortical neuron Anatomy 0.000 description 3
- 230000002950 deficient Effects 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 238000003745 diagnosis Methods 0.000 description 3
- 238000010494 dissociation reaction Methods 0.000 description 3
- 230000005593 dissociations Effects 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 210000001320 hippocampus Anatomy 0.000 description 3
- 102000054751 human RUNX1T1 Human genes 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 230000008105 immune reaction Effects 0.000 description 3
- 230000016784 immunoglobulin production Effects 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 231100000518 lethal Toxicity 0.000 description 3
- 230000001665 lethal effect Effects 0.000 description 3
- 230000027928 long-term synaptic potentiation Effects 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 229960000485 methotrexate Drugs 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 230000002887 neurotoxic effect Effects 0.000 description 3
- 238000005457 optimization Methods 0.000 description 3
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000002797 proteolythic effect Effects 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 230000007017 scission Effects 0.000 description 3
- 239000012679 serum free medium Substances 0.000 description 3
- 230000009870 specific binding Effects 0.000 description 3
- 210000004988 splenocyte Anatomy 0.000 description 3
- 239000012128 staining reagent Substances 0.000 description 3
- 238000010561 standard procedure Methods 0.000 description 3
- 238000002198 surface plasmon resonance spectroscopy Methods 0.000 description 3
- 238000013518 transcription Methods 0.000 description 3
- 230000035897 transcription Effects 0.000 description 3
- 238000001890 transfection Methods 0.000 description 3
- 238000011830 transgenic mouse model Methods 0.000 description 3
- 238000013519 translation Methods 0.000 description 3
- 108020005087 unfolded proteins Proteins 0.000 description 3
- 241001515965 unidentified phage Species 0.000 description 3
- 238000002255 vaccination Methods 0.000 description 3
- 230000003612 virological effect Effects 0.000 description 3
- KUWPCJHYPSUOFW-YBXAARCKSA-N 2-nitrophenyl beta-D-galactoside Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1OC1=CC=CC=C1[N+]([O-])=O KUWPCJHYPSUOFW-YBXAARCKSA-N 0.000 description 2
- NEGFNJRAUMCZMY-UHFFFAOYSA-N 3-(dimethylamino)benzoic acid Chemical compound CN(C)C1=CC=CC(C(O)=O)=C1 NEGFNJRAUMCZMY-UHFFFAOYSA-N 0.000 description 2
- XZKIHKMTEMTJQX-UHFFFAOYSA-N 4-Nitrophenyl Phosphate Chemical compound OP(O)(=O)OC1=CC=C([N+]([O-])=O)C=C1 XZKIHKMTEMTJQX-UHFFFAOYSA-N 0.000 description 2
- 102000009091 Amyloidogenic Proteins Human genes 0.000 description 2
- 108010048112 Amyloidogenic Proteins Proteins 0.000 description 2
- 108010039627 Aprotinin Proteins 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- 101150074155 DHFR gene Proteins 0.000 description 2
- 102000053602 DNA Human genes 0.000 description 2
- 241000283074 Equus asinus Species 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 108010020056 Hydrogenase Proteins 0.000 description 2
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 description 2
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 2
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 102000016943 Muramidase Human genes 0.000 description 2
- 108010014251 Muramidase Proteins 0.000 description 2
- 102000036675 Myoglobin Human genes 0.000 description 2
- 108010062374 Myoglobin Proteins 0.000 description 2
- 102000003505 Myosin Human genes 0.000 description 2
- 108060008487 Myosin Proteins 0.000 description 2
- 108010062010 N-Acetylmuramoyl-L-alanine Amidase Proteins 0.000 description 2
- 102000003729 Neprilysin Human genes 0.000 description 2
- 108090000028 Neprilysin Proteins 0.000 description 2
- 239000000020 Nitrocellulose Substances 0.000 description 2
- 108091028043 Nucleic acid sequence Proteins 0.000 description 2
- 108010058846 Ovalbumin Proteins 0.000 description 2
- 108700020962 Peroxidase Proteins 0.000 description 2
- 102000003992 Peroxidases Human genes 0.000 description 2
- 241000276498 Pollachius virens Species 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 108010003723 Single-Domain Antibodies Proteins 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 108010022394 Threonine synthase Proteins 0.000 description 2
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- 239000013504 Triton X-100 Substances 0.000 description 2
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 230000005875 antibody response Effects 0.000 description 2
- 229960004405 aprotinin Drugs 0.000 description 2
- 102000005936 beta-Galactosidase Human genes 0.000 description 2
- 108010005774 beta-Galactosidase Proteins 0.000 description 2
- 210000004899 c-terminal region Anatomy 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000010367 cloning Methods 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000002967 competitive immunoassay Methods 0.000 description 2
- 230000000536 complexating effect Effects 0.000 description 2
- 238000013270 controlled release Methods 0.000 description 2
- 239000002577 cryoprotective agent Substances 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 230000008021 deposition Effects 0.000 description 2
- 238000002405 diagnostic procedure Methods 0.000 description 2
- 230000029087 digestion Effects 0.000 description 2
- 102000004419 dihydrofolate reductase Human genes 0.000 description 2
- 239000002612 dispersion medium Substances 0.000 description 2
- 238000007877 drug screening Methods 0.000 description 2
- 238000001962 electrophoresis Methods 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 210000003527 eukaryotic cell Anatomy 0.000 description 2
- 230000036749 excitatory postsynaptic potential Effects 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 230000008014 freezing Effects 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 108020001507 fusion proteins Proteins 0.000 description 2
- 102000037865 fusion proteins Human genes 0.000 description 2
- 230000002949 hemolytic effect Effects 0.000 description 2
- 230000000971 hippocampal effect Effects 0.000 description 2
- 230000006801 homologous recombination Effects 0.000 description 2
- 238000002744 homologous recombination Methods 0.000 description 2
- FDGQSTZJBFJUBT-UHFFFAOYSA-N hypoxanthine Chemical compound O=C1NC=NC2=C1NC=N2 FDGQSTZJBFJUBT-UHFFFAOYSA-N 0.000 description 2
- 229940072221 immunoglobulins Drugs 0.000 description 2
- 229960001438 immunostimulant agent Drugs 0.000 description 2
- 239000003022 immunostimulating agent Substances 0.000 description 2
- 230000003308 immunostimulating effect Effects 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- ZPNFWUPYTFPOJU-LPYSRVMUSA-N iniprol Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@H]2CSSC[C@H]3C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC=4C=CC=CC=4)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC2=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]2N(CCC2)C(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N2[C@@H](CCC2)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N3)C(=O)NCC(=O)NCC(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N1)C(C)C)[C@@H](C)O)[C@@H](C)CC)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZPNFWUPYTFPOJU-LPYSRVMUSA-N 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 239000007951 isotonicity adjuster Substances 0.000 description 2
- 108010045069 keyhole-limpet hemocyanin Proteins 0.000 description 2
- 238000011813 knockout mouse model Methods 0.000 description 2
- 238000002372 labelling Methods 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 229920006008 lipopolysaccharide Polymers 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000008297 liquid dosage form Substances 0.000 description 2
- 229960000274 lysozyme Drugs 0.000 description 2
- 239000004325 lysozyme Substances 0.000 description 2
- 235000010335 lysozyme Nutrition 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 239000007758 minimum essential medium Substances 0.000 description 2
- 238000001823 molecular biology technique Methods 0.000 description 2
- 210000004498 neuroglial cell Anatomy 0.000 description 2
- 230000016273 neuron death Effects 0.000 description 2
- 229920001220 nitrocellulos Polymers 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 150000007523 nucleic acids Chemical class 0.000 description 2
- 229940092253 ovalbumin Drugs 0.000 description 2
- 230000036961 partial effect Effects 0.000 description 2
- 230000035790 physiological processes and functions Effects 0.000 description 2
- 229920001993 poloxamer 188 Polymers 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- RXWNCPJZOCPEPQ-NVWDDTSBSA-N puromycin Chemical compound C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO RXWNCPJZOCPEPQ-NVWDDTSBSA-N 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 230000002285 radioactive effect Effects 0.000 description 2
- 238000003127 radioimmunoassay Methods 0.000 description 2
- 239000002287 radioligand Substances 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 230000010076 replication Effects 0.000 description 2
- 238000002821 scintillation proximity assay Methods 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 208000002491 severe combined immunodeficiency Diseases 0.000 description 2
- KSAVQLQVUXSOCR-UHFFFAOYSA-M sodium lauroyl sarcosinate Chemical compound [Na+].CCCCCCCCCCCC(=O)N(C)CC([O-])=O KSAVQLQVUXSOCR-UHFFFAOYSA-M 0.000 description 2
- 239000007790 solid phase Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 210000001082 somatic cell Anatomy 0.000 description 2
- 230000000392 somatic effect Effects 0.000 description 2
- 210000000952 spleen Anatomy 0.000 description 2
- 238000012409 standard PCR amplification Methods 0.000 description 2
- 230000004936 stimulating effect Effects 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 238000010254 subcutaneous injection Methods 0.000 description 2
- 239000007929 subcutaneous injection Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 230000002103 transcriptional effect Effects 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- 241000701161 unidentified adenovirus Species 0.000 description 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- JWDFQMWEFLOOED-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 3-(pyridin-2-yldisulfanyl)propanoate Chemical compound O=C1CCC(=O)N1OC(=O)CCSSC1=CC=CC=N1 JWDFQMWEFLOOED-UHFFFAOYSA-N 0.000 description 1
- FXYPGCIGRDZWNR-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 3-[[3-(2,5-dioxopyrrolidin-1-yl)oxy-3-oxopropyl]disulfanyl]propanoate Chemical compound O=C1CCC(=O)N1OC(=O)CCSSCCC(=O)ON1C(=O)CCC1=O FXYPGCIGRDZWNR-UHFFFAOYSA-N 0.000 description 1
- BQWBEDSJTMWJAE-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 4-[(2-iodoacetyl)amino]benzoate Chemical compound C1=CC(NC(=O)CI)=CC=C1C(=O)ON1C(=O)CCC1=O BQWBEDSJTMWJAE-UHFFFAOYSA-N 0.000 description 1
- QRXMUCSWCMTJGU-UHFFFAOYSA-L (5-bromo-4-chloro-1h-indol-3-yl) phosphate Chemical compound C1=C(Br)C(Cl)=C2C(OP([O-])(=O)[O-])=CNC2=C1 QRXMUCSWCMTJGU-UHFFFAOYSA-L 0.000 description 1
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 description 1
- WQQBUTMELIQJNY-UHFFFAOYSA-N 1-[4-(2,5-dioxo-3-sulfopyrrolidin-1-yl)oxy-2,3-dihydroxy-4-oxobutanoyl]oxy-2,5-dioxopyrrolidine-3-sulfonic acid Chemical compound O=C1CC(S(O)(=O)=O)C(=O)N1OC(=O)C(O)C(O)C(=O)ON1C(=O)CC(S(O)(=O)=O)C1=O WQQBUTMELIQJNY-UHFFFAOYSA-N 0.000 description 1
- KJCVRFUGPWSIIH-UHFFFAOYSA-N 1-naphthol Chemical compound C1=CC=C2C(O)=CC=CC2=C1 KJCVRFUGPWSIIH-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- XSXWOBXNYNULJG-UHFFFAOYSA-N 2-(2,4,4-trimethylpentan-2-yl)phenol Chemical class CC(C)(C)CC(C)(C)C1=CC=CC=C1O XSXWOBXNYNULJG-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- BMYCCWYAFNPAQC-UHFFFAOYSA-N 2-[dodecyl(methyl)azaniumyl]acetate Chemical compound CCCCCCCCCCCCN(C)CC(O)=O BMYCCWYAFNPAQC-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- UAIUNKRWKOVEES-UHFFFAOYSA-N 3,3',5,5'-tetramethylbenzidine Chemical compound CC1=C(N)C(C)=CC(C=2C=C(C)C(N)=C(C)C=2)=C1 UAIUNKRWKOVEES-UHFFFAOYSA-N 0.000 description 1
- JRBJSXQPQWSCCF-UHFFFAOYSA-N 3,3'-Dimethoxybenzidine Chemical compound C1=C(N)C(OC)=CC(C=2C=C(OC)C(N)=CC=2)=C1 JRBJSXQPQWSCCF-UHFFFAOYSA-N 0.000 description 1
- AZKSAVLVSZKNRD-UHFFFAOYSA-M 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide Chemical compound [Br-].S1C(C)=C(C)N=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 AZKSAVLVSZKNRD-UHFFFAOYSA-M 0.000 description 1
- UMCMPZBLKLEWAF-BCTGSCMUSA-N 3-[(3-cholamidopropyl)dimethylammonio]propane-1-sulfonate Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCC[N+](C)(C)CCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 UMCMPZBLKLEWAF-BCTGSCMUSA-N 0.000 description 1
- HVYWMOMLDIMFJA-UHFFFAOYSA-N 3-cholesterol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)CCCC(C)C)C1(C)CC2 HVYWMOMLDIMFJA-UHFFFAOYSA-N 0.000 description 1
- HQFLTUZKIRYQSP-UHFFFAOYSA-N 3-ethyl-2h-1,3-benzothiazole-6-sulfonic acid Chemical compound OS(=O)(=O)C1=CC=C2N(CC)CSC2=C1 HQFLTUZKIRYQSP-UHFFFAOYSA-N 0.000 description 1
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 1
- TVZGACDUOSZQKY-LBPRGKRZSA-N 4-aminofolic acid Chemical compound C1=NC2=NC(N)=NC(N)=C2N=C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 TVZGACDUOSZQKY-LBPRGKRZSA-N 0.000 description 1
- IFBHRQDFSNCLOZ-YBXAARCKSA-N 4-nitrophenyl-beta-D-galactoside Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1OC1=CC=C([N+]([O-])=O)C=C1 IFBHRQDFSNCLOZ-YBXAARCKSA-N 0.000 description 1
- 206010069754 Acquired gene mutation Diseases 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 102000001049 Amyloid Human genes 0.000 description 1
- 108010094108 Amyloid Proteins 0.000 description 1
- 206010002023 Amyloidoses Diseases 0.000 description 1
- 206010059245 Angiopathy Diseases 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 108090001008 Avidin Proteins 0.000 description 1
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 1
- 102100021935 C-C motif chemokine 26 Human genes 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 102000014914 Carrier Proteins Human genes 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 206010008111 Cerebral haemorrhage Diseases 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 238000012286 ELISA Assay Methods 0.000 description 1
- 229920005682 EO-PO block copolymer Polymers 0.000 description 1
- 102000005593 Endopeptidases Human genes 0.000 description 1
- 108010059378 Endopeptidases Proteins 0.000 description 1
- YQYJSBFKSSDGFO-UHFFFAOYSA-N Epihygromycin Natural products OC1C(O)C(C(=O)C)OC1OC(C(=C1)O)=CC=C1C=C(C)C(=O)NC1C(O)C(O)C2OCOC2C1O YQYJSBFKSSDGFO-UHFFFAOYSA-N 0.000 description 1
- 108091029865 Exogenous DNA Proteins 0.000 description 1
- 241001295925 Gegenes Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 101000897493 Homo sapiens C-C motif chemokine 26 Proteins 0.000 description 1
- 101000611183 Homo sapiens Tumor necrosis factor Proteins 0.000 description 1
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- UGQMRVRMYYASKQ-UHFFFAOYSA-N Hypoxanthine nucleoside Natural products OC1C(O)C(CO)OC1N1C(NC=NC2=O)=C2N=C1 UGQMRVRMYYASKQ-UHFFFAOYSA-N 0.000 description 1
- 102000009786 Immunoglobulin Constant Regions Human genes 0.000 description 1
- 108010009817 Immunoglobulin Constant Regions Proteins 0.000 description 1
- 102000012745 Immunoglobulin Subunits Human genes 0.000 description 1
- 108010079585 Immunoglobulin Subunits Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102000013462 Interleukin-12 Human genes 0.000 description 1
- 108010065805 Interleukin-12 Proteins 0.000 description 1
- 102000000588 Interleukin-2 Human genes 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- 102000000704 Interleukin-7 Human genes 0.000 description 1
- 108010002586 Interleukin-7 Proteins 0.000 description 1
- FFEARJCKVFRZRR-UHFFFAOYSA-N L-Methionine Natural products CSCCC(N)C(O)=O FFEARJCKVFRZRR-UHFFFAOYSA-N 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- 229930195722 L-methionine Natural products 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241000239218 Limulus Species 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 1
- 241001045988 Neogene Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 102220606690 Neurotrimin_D23N_mutation Human genes 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 238000012408 PCR amplification Methods 0.000 description 1
- 239000005662 Paraffin oil Substances 0.000 description 1
- 102000057297 Pepsin A Human genes 0.000 description 1
- 108090000284 Pepsin A Proteins 0.000 description 1
- 201000005702 Pertussis Diseases 0.000 description 1
- 229920002732 Polyanhydride Polymers 0.000 description 1
- 229920000954 Polyglycolide Polymers 0.000 description 1
- 229920001710 Polyorthoester Polymers 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 101710118538 Protease Proteins 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 238000010240 RT-PCR analysis Methods 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 239000012722 SDS sample buffer Substances 0.000 description 1
- 102220538768 Superoxide dismutase [Cu-Zn]_E22G_mutation Human genes 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- 239000003070 absorption delaying agent Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 238000001042 affinity chromatography Methods 0.000 description 1
- 230000004520 agglutination Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- ILRRQNADMUWWFW-UHFFFAOYSA-K aluminium phosphate Chemical compound O1[Al]2OP1(=O)O2 ILRRQNADMUWWFW-UHFFFAOYSA-K 0.000 description 1
- WLDHEUZGFKACJH-UHFFFAOYSA-K amaranth Chemical compound [Na+].[Na+].[Na+].C12=CC=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(O)=C1N=NC1=CC=C(S([O-])(=O)=O)C2=CC=CC=C12 WLDHEUZGFKACJH-UHFFFAOYSA-K 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229960003896 aminopterin Drugs 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 206010002022 amyloidosis Diseases 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000919 anti-host Effects 0.000 description 1
- 230000009830 antibody antigen interaction Effects 0.000 description 1
- 238000011091 antibody purification Methods 0.000 description 1
- 238000009175 antibody therapy Methods 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 230000007503 antigenic stimulation Effects 0.000 description 1
- 239000012062 aqueous buffer Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- OHDRQQURAXLVGJ-HLVWOLMTSA-N azane;(2e)-3-ethyl-2-[(e)-(3-ethyl-6-sulfo-1,3-benzothiazol-2-ylidene)hydrazinylidene]-1,3-benzothiazole-6-sulfonic acid Chemical compound [NH4+].[NH4+].S/1C2=CC(S([O-])(=O)=O)=CC=C2N(CC)C\1=N/N=C1/SC2=CC(S([O-])(=O)=O)=CC=C2N1CC OHDRQQURAXLVGJ-HLVWOLMTSA-N 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 1
- DRTQHJPVMGBUCF-PSQAKQOGSA-N beta-L-uridine Natural products O[C@H]1[C@@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-PSQAKQOGSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000001588 bifunctional effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 229920000249 biocompatible polymer Polymers 0.000 description 1
- 239000013060 biological fluid Substances 0.000 description 1
- 150000001615 biotins Chemical class 0.000 description 1
- 230000006287 biotinylation Effects 0.000 description 1
- 238000007413 biotinylation Methods 0.000 description 1
- NXVYSVARUKNFNF-UHFFFAOYSA-N bis(2,5-dioxopyrrolidin-1-yl) 2,3-dihydroxybutanedioate Chemical compound O=C1CCC(=O)N1OC(=O)C(O)C(O)C(=O)ON1C(=O)CCC1=O NXVYSVARUKNFNF-UHFFFAOYSA-N 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- UDSAIICHUKSCKT-UHFFFAOYSA-N bromophenol blue Chemical compound C1=C(Br)C(O)=C(Br)C=C1C1(C=2C=C(Br)C(O)=C(Br)C=2)C2=CC=CC=C2S(=O)(=O)O1 UDSAIICHUKSCKT-UHFFFAOYSA-N 0.000 description 1
- 239000006189 buccal tablet Substances 0.000 description 1
- 239000004067 bulking agent Substances 0.000 description 1
- DQXBYHZEEUGOBF-UHFFFAOYSA-N but-3-enoic acid;ethene Chemical compound C=C.OC(=O)CC=C DQXBYHZEEUGOBF-UHFFFAOYSA-N 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 150000001767 cationic compounds Chemical class 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 230000007278 cognition impairment Effects 0.000 description 1
- 230000001149 cognitive effect Effects 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 238000003936 denaturing gel electrophoresis Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 230000001236 detergent effect Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- MUCZHBLJLSDCSD-UHFFFAOYSA-N diisopropyl fluorophosphate Chemical compound CC(C)OP(F)(=O)OC(C)C MUCZHBLJLSDCSD-UHFFFAOYSA-N 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- ZLFRJHOBQVVTOJ-UHFFFAOYSA-N dimethyl hexanediimidate Chemical compound COC(=N)CCCCC(=N)OC ZLFRJHOBQVVTOJ-UHFFFAOYSA-N 0.000 description 1
- FRTGEIHSCHXMTI-UHFFFAOYSA-N dimethyl octanediimidate Chemical compound COC(=N)CCCCCCC(=N)OC FRTGEIHSCHXMTI-UHFFFAOYSA-N 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- ZWIBGKZDAWNIFC-UHFFFAOYSA-N disuccinimidyl suberate Chemical compound O=C1CCC(=O)N1OC(=O)CCCCCCC(=O)ON1C(=O)CCC1=O ZWIBGKZDAWNIFC-UHFFFAOYSA-N 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 208000025688 early-onset autosomal dominant Alzheimer disease Diseases 0.000 description 1
- 238000004520 electroporation Methods 0.000 description 1
- 210000002257 embryonic structure Anatomy 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 206010014599 encephalitis Diseases 0.000 description 1
- 229940066758 endopeptidases Drugs 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 239000005038 ethylene vinyl acetate Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001400 expression cloning Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 208000015756 familial Alzheimer disease Diseases 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000005308 flint glass Substances 0.000 description 1
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 229960002743 glutamine Drugs 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 229960002449 glycine Drugs 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 108060003552 hemocyanin Proteins 0.000 description 1
- 229960002885 histidine Drugs 0.000 description 1
- 102000057041 human TNF Human genes 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 229940040731 human interleukin-12 Drugs 0.000 description 1
- 230000008348 humoral response Effects 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 230000005934 immune activation Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 238000003119 immunoblot Methods 0.000 description 1
- 238000010166 immunofluorescence Methods 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 238000012151 immunohistochemical method Methods 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 238000005462 in vivo assay Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000004941 influx Effects 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 150000002540 isothiocyanates Chemical class 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- GZQKNULLWNGMCW-PWQABINMSA-N lipid A (E. coli) Chemical compound O1[C@H](CO)[C@@H](OP(O)(O)=O)[C@H](OC(=O)C[C@@H](CCCCCCCCCCC)OC(=O)CCCCCCCCCCCCC)[C@@H](NC(=O)C[C@@H](CCCCCCCCCCC)OC(=O)CCCCCCCCCCC)[C@@H]1OC[C@@H]1[C@@H](O)[C@H](OC(=O)C[C@H](O)CCCCCCCCCCC)[C@@H](NC(=O)C[C@H](O)CCCCCCCCCCC)[C@@H](OP(O)(O)=O)O1 GZQKNULLWNGMCW-PWQABINMSA-N 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 210000001165 lymph node Anatomy 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 229960003646 lysine Drugs 0.000 description 1
- 235000018977 lysine Nutrition 0.000 description 1
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 210000002418 meninge Anatomy 0.000 description 1
- 201000011475 meningoencephalitis Diseases 0.000 description 1
- KBOPZPXVLCULAV-UHFFFAOYSA-N mesalamine Chemical compound NC1=CC=C(O)C(C(O)=O)=C1 KBOPZPXVLCULAV-UHFFFAOYSA-N 0.000 description 1
- 229960004963 mesalazine Drugs 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 229960004452 methionine Drugs 0.000 description 1
- MBAXWTVHCRPVFW-UHFFFAOYSA-N methyl 3-[(3-imino-3-methoxypropyl)disulfanyl]propanimidate Chemical compound COC(=N)CCSSCCC(=N)OC MBAXWTVHCRPVFW-UHFFFAOYSA-N 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 206010062198 microangiopathy Diseases 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 238000013365 molecular weight analysis method Methods 0.000 description 1
- 229940035032 monophosphoryl lipid a Drugs 0.000 description 1
- 239000012120 mounting media Substances 0.000 description 1
- 101150091879 neo gene Proteins 0.000 description 1
- 210000000944 nerve tissue Anatomy 0.000 description 1
- 230000000626 neurodegenerative effect Effects 0.000 description 1
- 230000004007 neuromodulation Effects 0.000 description 1
- 231100000189 neurotoxic Toxicity 0.000 description 1
- 230000000508 neurotrophic effect Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- JPXMTWWFLBLUCD-UHFFFAOYSA-N nitro blue tetrazolium(2+) Chemical compound COC1=CC(C=2C=C(OC)C(=CC=2)[N+]=2N(N=C(N=2)C=2C=CC=CC=2)C=2C=CC(=CC=2)[N+]([O-])=O)=CC=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=C([N+]([O-])=O)C=C1 JPXMTWWFLBLUCD-UHFFFAOYSA-N 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 229920002113 octoxynol Polymers 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000002892 organic cations Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000007310 pathophysiology Effects 0.000 description 1
- 229940111202 pepsin Drugs 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 125000001151 peptidyl group Chemical group 0.000 description 1
- 230000008447 perception Effects 0.000 description 1
- 210000005105 peripheral blood lymphocyte Anatomy 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920000729 poly(L-lysine) polymer Polymers 0.000 description 1
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229920002627 poly(phosphazenes) Polymers 0.000 description 1
- 230000008488 polyadenylation Effects 0.000 description 1
- 239000004633 polyglycolic acid Substances 0.000 description 1
- 229920002704 polyhistidine Polymers 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229940068977 polysorbate 20 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 239000008057 potassium phosphate buffer Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 210000001236 prokaryotic cell Anatomy 0.000 description 1
- 230000009465 prokaryotic expression Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 230000006920 protein precipitation Effects 0.000 description 1
- 229950010131 puromycin Drugs 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000010188 recombinant method Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012340 reverse transcriptase PCR Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 102200131541 rs121912450 Human genes 0.000 description 1
- 102200158871 rs33955330 Human genes 0.000 description 1
- 239000012146 running buffer Substances 0.000 description 1
- 239000012723 sample buffer Substances 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000010187 selection method Methods 0.000 description 1
- 239000008299 semisolid dosage form Substances 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 230000009131 signaling function Effects 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- 229940074404 sodium succinate Drugs 0.000 description 1
- ZDQYSKICYIVCPN-UHFFFAOYSA-L sodium succinate (anhydrous) Chemical compound [Na+].[Na+].[O-]C(=O)CCC([O-])=O ZDQYSKICYIVCPN-UHFFFAOYSA-L 0.000 description 1
- RPACBEVZENYWOL-XFULWGLBSA-M sodium;(2r)-2-[6-(4-chlorophenoxy)hexyl]oxirane-2-carboxylate Chemical compound [Na+].C=1C=C(Cl)C=CC=1OCCCCCC[C@]1(C(=O)[O-])CO1 RPACBEVZENYWOL-XFULWGLBSA-M 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 230000037439 somatic mutation Effects 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
- 238000003892 spreading Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- JJAHTWIKCUJRDK-UHFFFAOYSA-N succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate Chemical compound C1CC(CN2C(C=CC2=O)=O)CCC1C(=O)ON1C(=O)CCC1=O JJAHTWIKCUJRDK-UHFFFAOYSA-N 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 210000000225 synapse Anatomy 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- WGTODYJZXSJIAG-UHFFFAOYSA-N tetramethylrhodamine chloride Chemical class [Cl-].C=12C=CC(N(C)C)=CC2=[O+]C2=CC(N(C)C)=CC=C2C=1C1=CC=CC=C1C(O)=O WGTODYJZXSJIAG-UHFFFAOYSA-N 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 125000001493 tyrosinyl group Chemical class [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 description 1
- 229940045145 uridine Drugs 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
- C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
- C07K14/4711—Alzheimer's disease; Amyloid plaque core protein
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0007—Nervous system antigens; Prions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/005—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies constructed by phage libraries
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
- G01N33/6896—Neurological disorders, e.g. Alzheimer's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
- G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
- G01N2333/4701—Details
- G01N2333/4709—Amyloid plaque core protein
Definitions
- the invention also relates in the same way to derivatives of the oligomers, in particular crosslinked oligomers and oligomers based on truncated forms of the amyloid ⁇ (1-42) protein thereof, their preparation and their use.
- Amyloid ⁇ (1-42) protein also referred to as A ⁇ (1-42)
- a ⁇ is a central component of insoluble extracellular deposits (senile or neuritic plaques) composed of proteins, lipids, carbohydrates and salts in the brains of Alzheimer's disease and Down syndrome patients ( CL Masters et al. PNAS 82, 4245-4249, 1985 ).
- This protein which tends to polymerize in an aqueous environment, can exist in very different molecular forms.
- a ⁇ (1-42) -protofibrils are postulated. These are still soluble, fibrillar, more aggregated A ⁇ (1-42) forms with molecular weights in the range of 150-250 kDa ( Arispe et al. PNAS 90. 567 (1993 ) Lashuel et al., Nature 418, 291 (2002 )), which due to pore-forming properties should cause an uncontrolled influx of calcium through the membranes of neuronal cells.
- oligomeric A ⁇ (1-42) derivatives having molecular weights in the range of 15-30 kDa ( MP Lambert et al. PNAS 95, 6448-6453 (1998 )). These also as amyloid-derived, diffusible and contributing to dementia ligands (ADDL's for Amyloid Derived Dementing Ligands, see. US-A 6,218,506 and WO 01/10900 , or for Amyloid Derived Diffusive Ligands, cf. Lambert et al. supra ), non-fibrillar oligomers are found in preparations which have an inhibitory effect on the long-term potentiation rate of neurons in hippocampal slices.
- ADDL's for Amyloid Derived Dementing Ligands see. US-A 6,218,506 and WO 01/10900
- non-fibrillar oligomers are found in preparations which have an inhibitory effect on the long-term potentiation rate of neurons in hippocampal slices.
- At least two forms are discussed which, when subjected to gel electrophoretic analysis under non-denaturing conditions, have molecular weights in the range of from 27 to 28 kDa and 23 to 24 kDa ( US-A 6,218,506 ) or from about 26 kDa to 28 kDa ( WO 01/10900 ) or 17 kDa and 27 kDa ( MP Lambert et al. PNAS 95, 6448-6453 (1998 ) and SDSgelel electrophoretic analysis under denaturing conditions molecular weights of 17 kDa and 22 kDa ( MP Lambert et al.
- a disadvantage of the described manufacturing instructions is that they give inhomogeneous oligomer preparations.
- a ⁇ (1-42) responsible for neuromodulation have not yet been reproducibly provided, let alone unambiguously identified.
- N-terminally truncated forms of the A ⁇ (1-42) protein has been mentioned in connection with Alzheimer's disease.
- N-terminal truncated forms were detected in the deposits of brains of deceased Alzheimer's patients in addition to A ⁇ (1-42) ( C. Masters et al., PNAS 82, 4245-4249 (1985 )).
- certain proteases occurring in the brain such as neprilysin (NEP 24.11) or IDE (short for "insulin degrading enzymes" can degrade A ⁇ (1-42) ( DJ Selkoe, Neuron 32, 177-180, (2001 )).
- Antibodies directed against monomeric A ⁇ (1-42) protein and certain fragment thereof have already been described.
- the object of the present invention which is to provide the neuromodulatory and in particular neurone-damaging effect of A ⁇ (1-42) causative and in dementia diseases, such as Alzheimer's disease and Down's syndrome, increasingly occurring molecular forms, solves the invention by certain A ⁇ (1-42) oligomers obtainable in the form of homogeneous preparations with a specific process from monomeric A ⁇ (1-42) protein, as well as by certain derivatives of these oligomers, in particular cross-linked oligomers and oligomers based on truncated A ⁇ ( 1-42) forms.
- the preparation process makes it possible to convert poorly aqueous-soluble, peptide-synthetic A ⁇ (1-42) protein into defined soluble oligomers in high yield.
- the present invention therefore relates to the objects defined in the patent claims.
- the present invention relates to oligomers of the amyloid ⁇ (1-42) protein, wherein the oligomers in SDS gel electrophoresis have an apparent molecular weight of about 15 kDa, 20 kDa, 38 kDa and 48 kDa, respectively, or derivatives of the oligomers an optionally modified derivatization according to the molecular weight.
- Amyloid ⁇ (1-42) protein is a 42 amino acid polypeptide derived from amyloid precursor protein (APP) by proteolytic processing.
- APP amyloid precursor protein
- Isoforms of the amyloid ⁇ (1-42) protein thereto which occur in other organisms than humans, especially other mammals, especially rats.
- the present invention relates to oligomers of human amyloid ⁇ (1-42) proteins.
- Human amyloid ⁇ (1-42) proteins include in particular the protein having the amino acid sequence SEQ ID NO: 1, as well as muteins and allelic variants thereof, which are derived from said sequence, in particular by amino acid exchange.
- amino acid substitutions should be mentioned: A21 G, E22K, E22Q, E22G and D23N.
- the muteins or allelic variants of the amyloid ⁇ (1-42) protein according to the invention include, in particular, proteins having an amino acid sequence SEQ ID NO: 1 in which one or more amino acids selected from alanine 21, glutamic acid 22 and aspartic acid 23 other, preferably selected from glycine, lysine, glutamine and asparagine, amino acid are substituted.
- amino acids selected from alanine 21, glutamic acid 22 and aspartic acid 23 other preferably selected from glycine, lysine, glutamine and asparagine, amino acid are substituted.
- substitutions at position 22, in particular with glutamine or glycine are substitutions at position 22, in particular with glutamine or glycine.
- Rat amyloid ⁇ (1-42) proteins include, in particular, the protein having the amino acid sequence SEQ ID NO: 2, as well as muteins and allelic variants thereof, which are derived from said sequence, in particular by amino acid exchange.
- amino acid substitutions are to be mentioned, which correspond to the explained for the human sequence amino acid substitutions.
- the oligomers of the invention are obtainable by oligomerization of amyloid ⁇ (1-42) protein.
- the oligomerization involves a noncovalent aggregation of monomeric amyloid protein, so that it can be assumed that the oligomers according to the invention are composed of several amyloid ⁇ (1-42) protein monomers.
- the oligomers according to the invention have different molecular weights.
- apparent molecular weights can be assigned to the oligomers. These are about 15 kDa for the oligomer A1, about 20 kDa for the oligomer A2, about 38 kDa for the oligomer B1 and about 48 kDa for the oligomer B2, when gel electrophoresis under standard denaturing conditions (Tris-glycine gel, 4-20%, cf.
- Lambli UK Nature 227, 680-685 (1970 ), wherein the following standard proteins have the same apparent molecular weights under the same conditions: myosin 250 kDa, bovine serum albumin 98 kDa, glutamine hydrogenase 64 kDa, carboanhydrase 36 kDa, myoglobin 30 kDa, lysozyme 16 kDa, aprotinin 6 kDa, insulin B chain 4 kDa (see Blue Pre-stained Standard).
- the molecular weights for the oligomers B are about 64 to 90 kDa when subjected to gel electrophoresis under standard native conditions (Tris-glycine gel, 4-20%), the following standard proteins having the same apparent molecular weights under the same conditions: myosin 250 kDa, bovine serum albumin 98 kDa, glutamine hydrogenase 64 kDa, carboanhydrase 36 kDa, myoglobin 30 kDa, lysozyme 16 kDa, aprotinin 6 kDa, insulin B chain 4 kDa (see Blue Pre-stained Standard).
- the oligomers of the invention are characterized by an affinity for neuronal cells. It is believed that the oligomers bind to certain cell surface proteins, particularly receptors.
- the oligomers of the invention are characterized by a neuromodulating effect.
- This neuromodulating effect can manifest itself in particular in a reduced survival capacity of neuronal cells, for example neuroblastoma cells (neurotoxicity), if at least one oligomer according to the invention is allowed to act on a culture of these cells.
- the viability of the cells can be assessed in a manner known per se, for example by determining the extent of apoptosis caused by the action of the oligomers according to the invention. Suitable test methods, for example colorimetric methods based on 3- [4,5-dimethylthiazol-2-yl] -2,5-diphenyltetrazolium bromide (MTT), are available for this purpose.
- this neuromodulating effect can be manifested in particular in a modulation of the firing rate of neurons.
- oligomer according to the invention in the manner described above, e.g. in the form of one of the above-mentioned compositions.
- the cells or cellular structures are expediently provided in vitro, in particular as cell culture or, in the case of cellular structures, also as homogenates.
- Neuronal cells and in particular neuroblastoma cells serve to determine neurotoxicity.
- the cells may also be in vivo, especially as part of an organism, e.g. an experimental animal, or ex vivo.
- the condition of the cells is usually determined at least once before and at least once after exposure to the oligomer. If a comparison between the state before and the state after the action indicates a deviation, the tested oligomer has activity.
- the type of condition to be determined depends on the type of activity to be determined.
- Neurotoxicity can be determined by, for example, determining the survivability. For this purpose one can determine the proportion of living cells based on the total cell number before and after the action of the oligomer and compare with each other.
- the method is carried out at least twice, once in the presence of the test substance and once again without test substance.
- the test substance is added to the oligomers usually after their provision.
- the substance is expediently added even before the formation of the oligomers, ie even before their preparation, for example the educt (s) used for the oligomer formation.
- the preparation process of the invention with the addition of the test substance and then determine whether and to what extent the oligomers are formed. For this purpose, one can determine whether the process products obtained in this way have the properties of the oligomers according to the invention, that is, for example, have their molecular weight, binding capacity and activity.
- the oligomers B of the invention are to be preferred. Derivatives of these oligomers are also preferred in this respect, with particular emphasis on the oligomers based on an N-terminally shortened A ⁇ (1-42) protein.
- the oligomers A and the oligomers B may be obtained as a mixture in the form of compositions which in addition to the oligomers also low levels of other polypeptides, in particular monomeric amyloid ⁇ (1-42) protein and optionally also higher molecular forms aggregated amyloid - ⁇ (1-42) protein.
- Such compositions are likewise provided by the present invention and are distinguished, in particular, by the fact that the proportion of oligomer (s) according to the invention based on the totality of the proteins derived from the amyloid ⁇ (1-42) protein is at least 70% by weight. %, preferably at least 90 wt .-% and in particular at least 95 wt .-% is.
- the proportion of the oligomer A2 (20 kDa band in the SDS gel) is at least 50% by weight and preferably at least 70% by weight and in particular at least 85% by weight.
- the proportion of the oligomers B1 and B2 (38 kDa and 48 kDa bands in the SDS gel) is at least 60 wt .-%, preferably at least 75 wt .-% and in particular at least 90 wt .-%.
- the oligomers of the invention may also be derivatized.
- the purpose of such derivatizations may be, for example, to modulate the physicochemical properties of the oligomers, in particular with regard to bioavailability, to provide the oligomers with a detectable label or to immobilize, for example, to be coupled to the carrier. Labeling and immobilization are particularly important for diagnostic applications.
- Suitable markers well known in the protein biochemical field are well known to the person skilled in the art. These include fluorescence labels, for example certain fluorescein and tetramethylrhodamine derivatives, luminescent labels, colorimetric labels, radioactive labels and magnetic labels, and labels with affinity for complementary binding partners, such as biotin and streptavidin derivatives.
- the oligomer derivatives have molecular weights which may be correspondingly increased in comparison to the underivatized oligomers, but the aggregation number is the same.
- a biotin derivative based on the A ⁇ (1-42) oligomer B1 having a molecular weight in the 38 kDa SDS gel has a molecular weight of 42 kDa.
- Such cross-linked oligomers have the advantage that they are stabilized and their oligomerization is generally no longer reversible. They are therefore particularly suitable for use in diagnostic test systems or as an immunogen for the production of oligomer-specific antibodies.
- oligomers of the invention also include oligomers of fragments of the amyloid ⁇ (1-42) protein.
- Preferred are those fragments obtainable by the action of naturally occurring proteases.
- the fragments obtainable by proteolysis under non-denaturing conditions in physiological buffers have increased proteolytic stability compared to the amyloid ⁇ (1-42) protein.
- Preference is given to fragments obtainable by the action of endopeptidases.
- the fragments are obtainable by the action of trypsin, chymotrypsin, thermolysin, elastase, papain or endoproteinase GluC.
- those fragments are preferred whose oligomers according to the invention by a neuromodulating Effect are marked.
- preferred fragments are characterized in particular by being derived from the amyloid ⁇ (1-42) protein by cleavage of N-terminal sequences.
- these N-terminal sequences may be fragments of up to 23, preferably up to 21 and most preferably up to 19 amino acids of the N-terminal sequence of the amyloid ⁇ (1-42) protein.
- preference is given to fragments of the A ⁇ (1-42) protein whose sequence comprises amino acids 24 to 42, preferably 22 to 42 and in particular 20 to 42, in continuous sequence.
- the N-terminal sequences to be cleaved may be sequences having at least 7, preferably at least 9, and most preferably at least 11 amino acids of the N-terminal sequence of the amyloid ⁇ (1-42) protein.
- fragments of the amyloid ⁇ (1-42) protein are preferred, which are shortened N-terminally by 7 to 23, preferably 9 to 21 and in particular 11 to 19 amino acids. These fragments correspond to the formula A ⁇ (x-42), where x is 8 to 24, preferably 10 to 22 and especially 12 to 20.
- Derivatives of the invention also include those derived from an amyloid ⁇ (1-42) protein having C-terminal 1 or 2 further amino acids.
- oligomers of the A ⁇ (1-43) protein or the above include corresponding derivatives thereof.
- the process according to the invention for the preparation of the oligomers may comprise essentially three steps, of which the first step is optional but advantageous, the second step for the preparation of the oligomers A and B is mandatory and the third step is the preparation of the oligomers B according to the invention.
- Step 1 concerns the unfolding of the protein.
- hydrogen bond-breaking agents such as hexafluoroisopropanol (HFIP)
- DMSO dimethyl sulfoxide
- the stock suspension can be temporarily stored at low temperature, for example at about -20 ° C.
- the protein can be taken up in a slightly acidic, preferably aqueous solution, for example an about 10 mM aqueous HCl solution. After an incubation period of generally a few minutes, insoluble constituents are centrifuged off. A few minutes at 10,000 g are appropriate. These process steps are preferably carried out at room temperature, i. a temperature in the range of 20 to 30 ° C performed. The supernatant obtained after centrifugation contains the amyloid ⁇ (1-42) protein and can be temporarily stored at low temperature, for example at about -20 ° C.
- Step 2 relates to the oligomerization of the protein to the oligomers A.
- a detergent is allowed to act on the optionally at least partially unfolded protein until sufficient oligomer A is formed.
- ionic detergents in particular anionic detergents.
- Detergents of the formula (I) in which R is unbranched alkyl are advantageous, of which in particular alk-1-yl radicals may be mentioned. Particularly preferred is sodium dodecyl sulfate (SDS). Also lauric acid and oleic acid can be used advantageously. Particularly advantageous are the Na salt of the detergent is lauroylsarcosine (also known as sarkosyl NL-30 or Gardol ®).
- the exposure time of the detergent depends on whether - and if so, to what extent - the protein introduced into the oligomerization is unfolded. If the protein according to step 1 previously treated with a hydrogen bond-breaking agent, ie in particular with hexafluoroisopropanol, sufficient exposure times in the range of a few hours, advantageously about 1 to 20 and in particular about 2 to 10 hours then when the exposure temperature about 20 to 50 ° C and in particular about 35 to 40 ° C. If less or essentially unfolded protein is assumed, correspondingly longer exposure times are expedient.
- a hydrogen bond-breaking agent ie in particular with hexafluoroisopropanol
- amyloid ⁇ (1-42) protein has been pretreated according to the procedure outlined above as an alternative to step 1, or if it is entered directly in step 2, exposure times will range from about 5 to 30 hours and more preferably from about 10 to 20 hours then when the exposure temperature is about 20 to 50 ° C and especially about 35 to 40 ° C. After incubation, insoluble constituents are advantageously centrifuged off. A few minutes at 10,000 g are appropriate.
- the selected detergent concentration depends on the detergent used. When SDS is used, a concentration in the range of 0.01 to 1% by weight, preferably 0.05 to 0.5% by weight, for example, about 0.2% by weight, proves useful. If lauric acid or oleic acid are used, somewhat higher concentrations are expedient, for example in a range from 0.05 to 2% by weight, preferably from 0.1 to 0.5% by weight, for example from about 0.5% by weight. %.
- the action of the detergent should be at a salt concentration approximately in the physiological range.
- NaCl concentration in the range of 50 to 500 mM, preferably 100 to 200 mM and especially at about 140 mM are useful.
- the oligomers A ie in particular the oligomers A1 and / or A2 containing solution can be temporarily stored at low temperature, for example at about -20 ° C.
- it can be fed to the oligomers B according to the invention or the further reaction, or further work-up or purification steps can initially follow, with which, in particular, a further enrichment of at least one the oligomers A of the invention is achieved.
- the oligomers according to the invention can be separated from further protein constituents which contain the solution and in particular those which are derived from the amyloid ⁇ (1-42) protein.
- affinity chromatographic methods are suitable for this purpose, in which, for example, specific antibodies, ie in particular also the oligomer-specific antibodies according to the invention, can be used.
- Step 3 relates to the oligomerization to the oligomers B.
- a composition containing oligomer A is selected as starting material for this step.
- the oligomers A have meaning according to the invention as intermediates for the preparation of the oligomers B. If this composition comes from step 2, it regularly contains detergent and a salt concentration in the physiological range. Then it is appropriate to reduce the detergent effect or the salt concentration. This can be achieved by reducing the detergent or salt concentration, e.g. by dilution, conveniently with water or a buffer of lower salt concentration, eg. B. Tris-HCl, pH 7.3, take place.
- Dilution factors in the range of about 2 to 10, advantageously in the range of about 3 to 8 and in particular of about 4 have been found to be suitable.
- the reduction of detergency can also be achieved by the addition of substances which can neutralize detergency.
- substances capable of complexing the detergents such as substances capable of stabilizing cells in the course of purification and extraction procedures, e.g. certain EO / PO block copolymers, in particular the block copolymer guided under the trade name Pluronic® F 68.
- alkoxylated and in particular ethoxylated alkylphenols such as the ethoxylated t-octylphenols of the Triton® X series, in particular Triton® X100, 3- (3-cholamidopropyl-dimethylammonio) -1-propanesulfonate (CHAPS®) or alkoxylated and in particular ethoxylated sorbitan fatty acid esters such as those of the Tween® series, in particular Tween® 20, in concentration ranges in the range or above the respective critical micelle concentration.
- ethoxylated alkylphenols such as the ethoxylated t-octylphenols of the Triton® X series, in particular Triton® X100, 3- (3-cholamidopropyl-dimethylammonio) -1-propanesulfonate (CHAPS®) or alkoxylated and in particular ethoxylated sorbitan
- the solution is incubated until sufficient oligomer B has formed. Exposure times in the range of several hours, preferably in the range of about 10 to 30 hours and in particular in the range of about 15 to 25 hours are sufficient if the exposure temperature about 20 to 50 ° C and in particular about 35 to 40 ° C. Then you can concentrate the solution and spin off any residues. Again, prove to be a few minutes at 10,000 g as appropriate. The supernatant obtained after centrifugation contains oligomers B.
- the oligomers B may first be precipitated from the detergent-containing solution, recovered and redissolved in detergent-free medium. Measures for precipitation of proteins are well known to those skilled in the art. According to the invention, the addition of aqueous methanolic acetic acid has proven to be expedient. Without being bound by any particular mechanism, detergent or salt variation appears to bring the protein into definite soluble forms which clearly differ from the starting form of the protein dissolved in aqueous physiological buffers, e.g. by denaturing or native gel electrophoresis or gel permeation chromatography. This is surprising since detergents normally disaggregate protein aggregates, i. H. subdivided into subunits, whereas according to the invention, starting from a monomer tending to aggregate defined oligomers are obtained.
- the crosslinking of oligomers according to the invention or derivatives thereof can be carried out in a manner known per se. If, for example, glutaric dialdehyde is used as the crosslinking agent, one from process step 2 according to the invention can be used or 3 resulting solution with a glutaric dialdehyde solution. After a few hours at room temperature, the oligomers reacted with the glutaraldehyde. The reaction can then be stopped in a manner known per se by reacting the excess glutaric dialdehyde with reagents generally known for this purpose, such as ethanolamine. Depending on whether the oligomers A or B according to the invention are cross-linked, a solution of crosslinked oligomers according to the invention which are denoted by A-CL or B-CL is obtained.
- the optionally cross-linked oligomers B or derivatives thereof it is possible, following their synthesis, to increase the salt concentration again without impairing the stability of the oligomers. This is important in view of the use of the oligomers, for example in the case that in use physiological conditions are appropriate (cellular applications, in vivo applications).
- oligomers of fragments of the amyloid ⁇ (1-42) protein can be prepared by proteolysis, either starting from corresponding monomer fragments by oligomerization or starting from oligomers of the amyloid ⁇ (1-42) protein.
- a solution resulting from the process steps 2 or 3 according to the invention can be treated with protease.
- the protease is inactivated in a generally known manner.
- the resulting oligomers can then be obtained on the basis of procedures already described here and, if necessary, further processed by further work-up or purification steps.
- novel oligomers and the compositions containing them are characterized by their homogeneity and stability. They are soluble in physiological media, eg, physiological saline, and differ from fibrillar forms in their more globular appearance. They have the advantage of having a spatial structure that differs markedly from other A ⁇ (1-42) forms, especially the monomer, non-toxic oligomers, the A ⁇ (1-42) APP precursor molecule, protofibrils and fibrils. They are therefore particularly suitable for the generation of specific antibodies both in vivo and in vitro and allow, for example, a specific active immunization. It may be crucial to use for immunization only those oligomers that are responsible for the disease.
- a ⁇ (1-42)
- the monomeric molecule or smaller oligomers may be necessary for important signaling functions in the organism be.
- the removal of the fibrillar deposits, which are believed to be important for the lining of the cells, can damage the organism.
- oligomers of the invention possess diagnostic and therapeutic value due to their involvement in amyloid ⁇ -protein associated physiological processes.
- the use of oligomers according to the invention and derivatives thereof, optionally in the form of a corresponding composition, in diagnostic in vitro and in vivo detection methods is the subject of the present invention.
- Amyloid ⁇ -protein-associated physiological processes include those associated with deposition of amyloid proteins (amyloidoses). These include both those processes that lead to structural changes of nerve tissue and are important, for example, in Alzheimer's disease and Down's syndrome, as well as those processes that affect other tissues, such as amyloid microangiopathies, such as Congophilic amyloid angiopathy (CAA ).
- amyloidoses include those associated with deposition of amyloid proteins (amyloidoses). These include both those processes that lead to structural changes of nerve tissue and are important, for example, in Alzheimer's disease and Down's syndrome, as well as those processes that affect other tissues, such as amyloid microangiopathies, such as Congophilic amyloid angiopathy (CAA ).
- CAA Congophilic amyloid angiopathy
- the oligomers according to the invention based on truncated forms of the A ⁇ (1-42) protein are of particular importance: because of the lacking N-terminus, a significantly more selective immune response can be generated with them than with the A ⁇ (1-42) protein. While the highly immunogenic N-terminus in the classical A ⁇ (1-42) protein predominantly results in antibodies specific for this region of the molecule, eg the antibodies 6E10 (F.
- One aspect of this use is the generation of oligomer-specific antibodies as part of a therapy.
- a further object of the present invention is the use of an oligomer or derivative thereof according to the invention in the therapeutic field, in particular as a vaccine.
- Such a vaccine is usually a pharmaceutical composition containing at least one oligomer according to the invention and / or at least one derivative thereof according to the invention.
- a pharmaceutical composition containing at least one oligomer according to the invention and / or at least one derivative thereof according to the invention.
- one of the inventive, two or more oligomer-containing compositions, or a combination of different compositions can be used.
- the composition may contain a physiologically acceptable carrier and optionally other excipients, for example immunostimulants.
- the vaccines according to the invention can be formulated in particular in a form suitable for parenteral, for example intravenous, intramuscular and subcutaneous administration.
- the carrier preferably contains water, saline, alcohol, a fat, a wax and / or a buffer.
- an adjuvant may be included.
- Most adjuvants contain a substance intended to protect the antigen from rapid catabolism, such as aluminum hydroxide or a mineral oil, as well as lipid A, Bortadella pertussis or Mycobacterium tuberculosis-derived protein.
- Suitable adjuvants are usually commercially available, for example complete or incomplete Freund's adjuvant; AS-2; Aluminum salts such as aluminum hydroxide (optionally gel) or aluminum phosphate; Calcium, iron or zinc salts; an insoluble suspension of acylated tyrosine; acylated sugars; cationically or anionically derivatized polysaccharides; polyphosphazenes; biodegradable microspheres; Monophosphoryl lipid A.
- Cytokines such as GM-CSF or interleukin-2, -7 or -12 can also be used as adjuvants.
- oligomers or oligomer derivatives to be used are not or only weakly immunogenic, their immunogenicity can be increased by adding them to carriers, preferably a carrier protein, such as keyhole limpet hemocyanin (KLH), limulus polyphenus hemocyanin ((LPH), Bovine serum albumin (BSA) or ovalbumin (OVA), for example, may be useful to those skilled in the art, such as reaction with glutaric dialdehyde, for example by incubation of the oligomer or oligomer mixture with a suitable peptide or peptide mixture in water or an aqueous solvent.
- KLH keyhole limpet hemocyanin
- LPH limulus polyphenus hemocyanin
- BSA Bovine serum albumin
- OVA ovalbumin
- This reaction may conveniently be carried out at ambient temperature, usually room temperature, but it may also be convenient to cool or slightly heat it, usually within a few hours to the desired result, a reaction time of, for example 2 h is in the
- the components to be used are first combined. It is advantageous to first incubate the resulting component mixture. This is conveniently done at ambient temperature, usually at room temperature. However, it may be convenient to cool or slightly heat the mixture. The incubation period is usually a few minutes to a few hours, an incubation period of 1 h has proved to be advantageous.
- immunization cocktails will generally contain other adjuvants, especially adjuvants commonly used for immunization, e.g. Freund's adjuvant.
- adjuvants commonly used for immunization e.g. Freund's adjuvant.
- complete Freund's adjuvant is used for the first immunization whereas all further immunizations are performed with incomplete Freund's adjuvant.
- the antigen preferably as a component mixture described above, is added to the excipient (s). As a rule, the antigen is emulsified.
- Rodents or even rabbits are particularly suitable as hosts. These or other suitable hosts are injected with the immunization cocktails, preferably subcutaneously.
- the antibody titers can be determined by an immunoassay, for example, competitive with a sheep anti-host IgG and labeled oligomer.
- a particular host is suitable for antibody production. For example, if four immunizations are performed, one can determine the antibody titer after the third immunization and then obtain antibodies from animals that have sufficient antibody titer.
- B lymphocytes Part of a mammalian immune system is B lymphocytes, which as a whole contain an antibody repertoire composed of hundreds of millions of different antibody specificities.
- a normal immune response against a particular antigen means the selection of one or more antigen-specifically binding antibodies from that repertoire, and the success of an immune response is based, at least in part, on the ability of those antibodies to specifically recognize (and eventually eliminate) the stimulatory antigen. while ignoring other molecules from the environment of the antibodies.
- the antigen of interest may be allowed to act on the antibody repertoire either in vivo or in vitro .
- the antigen is allowed to act on the repertoire by immunizing an animal with the antigen in vivo .
- This in vivo approach may further involve establishing a series of hybridomas from the lymphocytes of an animal and selecting a hybridoma which secretes an antibody specifically binding the antigen.
- the animal to be immunized may be, for example, a mouse, rat, rabbit, chicken, camelid or sheep or a transgenic version of any of the aforementioned animals, for example, a human immunoglobulin gene transgenic mouse that makes human antibodies to an antigenic stimulus.
- mice with severe combined immunodeficiency that have been reconstituted with human peripheral blood mononuclear cells (chimeric hu-PBMC-SCID mice) or with lymphoid cells or progenitors thereof, as well as Mice treated with lethal whole body irradiation, then protected against radiation with bone marrow cells from a mouse with severe combined immunodeficiency (SCID) and subsequently transplanted with functional human lymphocytes (the so-called Trimera system).
- SCID severe combined immunodeficiency
- Another type of animal to be immunized is an animal (eg, a mouse) in the genome of which an endogenous gene encoding the antigen of interest has been knocked out, eg, by homologous recombination, such that this animal is immunized with the antigen recognizes the antigen as foreign.
- an animal eg, a mouse
- an endogenous gene encoding the antigen of interest has been knocked out, eg, by homologous recombination, such that this animal is immunized with the antigen recognizes the antigen as foreign.
- the polyclonal or monoclonal antibodies produced by these methods can be characterized and selected using known screening techniques, including, but not limited to, ELISA techniques.
- the antigen is allowed to act on the antibody repertoire in vitro by screening a recombinant antibody library with the antigen.
- the recombinant antibody library may be expressed on the surface of bacteriophages or on the surface of yeast cells or on the surface of bacterial cells.
- the recombinant antibody library is, for example, an scFv library or a Fab library.
- antibody libraries are expressed as RNA-protein fusions.
- the antigen can be allowed to act on the antibody repertoire by immunizing an animal with the antigen in vivo, and then recombinant antibody library or single domain antibody library (eg, heavy and / or light chain) prepared from lymphoid cells of the animal Antigen screent in vitro .
- the antigen is allowed to act on the antibody repertoire by immunizing an animal with the antigen in vivo and then affinity maturing a recombinant antibody library or single domain library prepared from lymphoid cells of the animal.
- the antigen is allowed to act on the antibody repertoire by immunizing an animal with the antigen in vivo , then selecting individual antibody-producing cells which secrete an antibody of interest and recovering from these selected cells cDNAs for the heavy and light chain variable region (eg by PCR) and the heavy and light variable regions Chain is expressed in vitro in mammalian host cells (referred to as the lymphocyte antibody selection method, or SLAM for "Selected Lymphocyte Antibody Method"), allowing the selected antibody gene sequences to be further selected and manipulated.
- monoclonal antibodies can be selected by expression cloning by expressing the heavy and light chain antibody genes in mammalian cells and selecting those mammalian cells which secrete an antibody of the desired binding affinity.
- those polyclonal and monoclonal antibodies can be selected which bind an oligomer or derivative thereof, but not other forms of the A (1-42) protein, APP, amyloid fibrils or amyloid plaques and a number of other unrelated antigens and tissues ,
- the person skilled in the art is well aware that antibody selections are based on well-defined antigens. However, if less well-defined antigens are used, they are not selective enough. In short, in vitro exposure and selection are similar to affinity chromatography, separating "ligands" for the desired antigen from those that do not bind the antigen with sufficient affinity. The degree of enrichment of the desired antibodies from the vast pool of other antibodies is therefore a direct consequence of antigen quality.
- the oligomers and derivatives thereof according to the invention are antigens with which appropriate, relevant and selective antibodies accumulate and effectively separate from antibodies which recognize other forms related to the A (1-42) protein as well as other unrelated antigens to let.
- monoclonal antibodies can be isolated by standard techniques, such as those originally developed by Kohler and Milstein (1975, Nature 256: 495-497 ) (see also Brown et al. (1981) J. Immuno / 127: 539-46 ; Brown et al. (1980) J Biol Chem 255: 4980-83 ; Yeh et al. (1976) PNAS 76: 2927-31 ; and Yeh et al. (1982) Int. J. Cancer 29: 269-75 ) described hybridoma technique.
- an immortalized cell line (typically a myeloma) is fused with lymphocytes (typically splenocytes or lymph node cells or peripheral blood lymphocytes) of a mammal immunized with the oligomer or derivative thereof of the invention, and the culture supernatants of the resulting hybridoma cells are screened to identify a hybridoma which a monoclonal antibody having specificity for oligomer according to the invention or for a derivative thereof produced.
- lymphocytes typically splenocytes or lymph node cells or peripheral blood lymphocytes
- the immortalized cell line eg, a myeloma cell line
- the immortalized cell line is derived from the same mammalian species as the lymphocytes.
- murine hybridomas can be established by fusing lymphocytes from a mouse immunized with an immunogenic preparation of the invention to an immortalized mouse cell line.
- Preferred immortalized cell lines are mouse myeloma cell lines which are sensitive to hypoxanthine, aminopterin and thymidine-containing culture medium (HAT medium).
- myeloma cell lines can be used as standard by fusion, eg the P3-NS1 / 1-Ag4-1, P3-x63-Ag8.653 or Sp2 / O-Ag14 myeloma line.
- These myeloma cell lines are available from the American Type Culture Collection (ATCC), Rockville, MD.
- ATCC American Type Culture Collection
- HAT-sensitive mouse myeloma cells are fused to mouse splenocytes using polyethylene glycol (PEG).
- PEG polyethylene glycol
- the from the Fusion-resultant hybridoma cells are then selected using HAT medium, killing unfused and non-productively fused myeloma cells (unfused splenocytes die after several days as they are untransformed).
- Monoclonal antibody-producing hybridoma cells specifically recognizing oligomer or derivative thereof of the present invention are identified by screening the hybridoma culture supernatants for such antibodies, eg, by using a standard ELISA assay to select those antibodies, the oligomer of the invention or a derivative thereof can specifically bind.
- mice can be used for in vivo immunization.
- a host expressing an endogenous version of the antigen of interest itself may be used.
- a host deficient for an endogenous version of the antigen of interest may be used. It has been shown, for example, that mice made deficient for a particular endogenous protein (ie, knockout mice) via homologous recombination on the corresponding endogenous gene produce a humoral response to the protein with which they were immunized, and thus to produce high affinity monoclonal antibodies
- Antibodies to the protein can be used (see, eg Roes, J. et al. (1995) J. Immunol. Methods 183: 231-237 ; Lunn, MP et al. (2000) J. Neurochem. 75: 404-412 ).
- non-human mammals are useful as hosts for antibody production. These include mice, rats, chickens, camelids, rabbits and goats (and knockout versions thereof), although mice are preferred for hybridoma production.
- non-human host animal expressing a human antibody repertoire.
- Such non-human animals include transgenic animals (e.g., mice) carrying human immunoglobulin transgenes (chimeric hu-PBMC-SCID mice) and human / mouse irradiation chimeras, described in more detail below.
- the animal immunized with an oligomer or derivative thereof of the invention is a non-human mammal, preferably a mouse, that is transgenic by human immunoglobulin genes such that the non-human mammal makes human antigens following an antigenic stimulus.
- human immunoglobulin genes such that the non-human mammal makes human antigens following an antigenic stimulus.
- heavy and light chain human immunoglobulin immunoglobulin transgenes are introduced into such animals with the human germline configuration Animals have been altered so that their endogenous loci for heavy and light chain are inactive. Stimulating such animals with antigen (eg, with a human antigen) produces antibodies derived from the human immunoglobulin sequences (ie, human antibodies). From the lymphocytes of such animals, human monoclonal antibodies can be made by standard hybridoma technology.
- the animal immunized with the oligomer or derivative thereof of the invention may be a severe combined immunodeficiency (SCID) mouse reconstituted with human peripheral blood mononuclear cells or lymphoid cells or progenitors thereof.
- SCID severe combined immunodeficiency
- Such mice termed chimeric hu-PBMC-SCID mice, have been shown to produce human immunoglobulin responses to an antigenic stimulus.
- chimeric hu-PBMC-SCID mice have been shown to produce human immunoglobulin responses to an antigenic stimulus.
- the animal which is immunized with oligomer according to the invention or a derivative thereof is a mouse which is lethal Irradiated with bone marrow cells from mice with severe combined immunodeficiency (SCID) and then transplanted with functional human lymphocytes.
- SCID severe combined immunodeficiency
- This type of chimera called the Trimera system, is used to make human monoclonal antibodies by immunizing the mice with the antigen of interest and then producing monoclonal antibodies using standard hybridoma technology.
- these mice and their use for the production of antibodies see for example Eren, R. et al. (1998) Immunology 93: 154-161 ; Reisner, Y and Dagan, S. (1998) Trends Biotechnol. 16: 242-246 ; Ilan, E. et al. (1999) Hepatology 29: 553-562 ; and Bocher, WO et al. (1999) Immunology 96: 634-641 ,
- antibodies according to the invention can be identified and isolated by screening recombinant immunoglobulin library combiners with an oligomer or derivative thereof according to the invention, thus members of the immunogiobulin library specific to the oligomer or derivative thereof, to isolate.
- Kits for generating and screening display banks are commercially available (eg, the Recombinant Phage Antibody System from Pharmacia, Catalog No. 27-9400-01, and the SurfZAP® Phage Display Kit from Stratagene, Catalog No. 240612).
- the display bank is an scFv bank or a fab bank. The phage display technique for screening recombinant antibody libraries has been well described.
- WO 97/29131 (describes the preparation of a recombinant human Antibody to a human antigen (human tumor necrosis factor alpha), as well as in vitro affinity maturation of the recombinant antibody) and Salfeld et al. US Provisional Application No. 60 / 126,603 and the patent applications based thereon (also describes the production of recombinant human antibodies to human antigen (human interleukin-12), as well as the in vitro affinity maturation of the recombinant antibody).
- recombinant antibody libraries can be expressed on the surface of yeast cells or bacterial cells.
- Methods for making and screening benches that are expressed on the surface of yeast cells are known in U.S. Pat WO 99/36569 described.
- Methods for making and screening banks that are expressed on the surface of bacterial cells are known in U.S. Pat WO 98/49286 described in more detail.
- the DNAs encoding the antibody light and heavy chains are isolated by standard molecular biology techniques, for example, by PCR amplification of DNA from the display package (eg, the phage) isolated during the screening of the bank.
- Nucleotide sequences of genes for light and heavy antibody chains, with which PCR primers can be prepared, are known in the art. Many such sequences are for example in Kabat, EA, et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242 and the database for sequences of the human germ line VBASE.
- An antibody or antibody portion of the invention may be produced by recombinantly expressing the genes for immunoglobulin light and heavy chains in a host cell.
- a Host cell is transfected with one or more recombinant expression vectors bearing DNA fragments encoding the antibody light and heavy immunoglobulin chains such that the light and heavy chains are expressed in the host cell and preferably into the medium in which the host cells are cultured; be secreted. From this medium, the antibodies can be obtained.
- Standardized recombinant DNA methodology is used to obtain genes for heavy and light antibody chains, to insert these genes into recombinant expression vectors, and to introduce the vectors into host cells.
- DNA fragments encoding the VH and VL segments of the antibody of interest can be further manipulated with standard recombinant DNA techniques, such as the variable region genes in full length antibody chain genes To convert genes for Fab fragments or into a scFv gene.
- a VL or VH-encoding DNA fragment is operatively linked to another another protein, e.g. linked to a constant antibody region or a flexible linker, encoding DNA fragment.
- the term "operatively linked” is intended to mean that the two DNA fragments are linked together in such a way that the amino acid sequences encoded by the two DNA fragments remain in-frame.
- the isolated DNA encoding the VH region can be converted into a full-length heavy chain gene by encoding the VH region-encoding DNA with another DNA heavy chain constant region (CH1, CH2 and CH3) operatively linked.
- CH1, CH2 and CH3 DNA heavy chain constant region
- the sequences of human heavy chain constant region genes are well known (see, eg Kabat, EA, et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242 ), and DNA fragments spanning these regions can be obtained by standard PCR amplification.
- the heavy chain constant region may be a constant region of IgG1, IgG2, IgG3, IgG4, IgA, IgE, IgM or IgD, with a constant region of IgG1 or IgG4 being preferred.
- the VHcoding DNA can be operatively linked to another DNA molecule which only codes for the constant region CH1 of the heavy chain.
- the isolated DNA encoding the VL region can be converted into a full-length light chain gene (as well as a Fab light chain gene) by mixing the VL-encoding DNA with another, the CL constant region Chain-coding DNA molecule operatively linked.
- the sequences of human light chain constant region genes are well known (see Kabat, EA, et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242 ), and DNA fragments spanning these regions can be obtained by standard PCR amplification.
- the constant region of the light chain may be a constant kappa or lambda region, with a constant kappa region being preferred.
- the VH and VL-encoding DNA fragments can be operatively linked to another fragment that encodes a flexible linker, eg, the amino acid sequence (Gly 4 -Ser) 3 , such that the VH and VL Sequences are expressed as a continuous single-chain protein, with the VL and VH regions linked together via the flexible linker (see Bird et al. (1988) Science 242: 423-426 ; Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85: 5879-5883 ; McCafferty et al., Nature (1990) 348: 552-554 ).
- a flexible linker eg, the amino acid sequence (Gly 4 -Ser) 3
- VH and VL single domains having specificity for oligomer of the invention or a derivative thereof can be isolated from single domain libraries by the methods described above.
- Two VH single domain chains (with or without CH1) or two VL chains or a pair of VH and VL chains of the desired specificity can be used to remove oligomers or derivatives thereof of the invention from the body.
- the DNAs encoding the partial and full length light and heavy chains can be inserted into expression vectors such that the genes are operably linked to transcriptional and translational control sequences.
- operably linked is intended to mean that an antibody gene is ligated in a vector such that transcriptional and translational control sequences within the vector fulfill their intended function of regulating the transcription and translation of the antibody gene.
- the expression vector and expression control sequences are chosen to be compatible with the expression host cell used.
- the gene for the The antibody light chain and antibody heavy chain gene can be inserted into separate vectors, or both genes are inserted into the same expression vector, which is the usual case.
- the antibody genes are inserted into the expression vector by standard methods (eg, ligation of complementary restriction sites on the antibody gene fragment and vector, or blunt-ended ligation if no restriction sites are present).
- the expression vector may already carry constant antibody region sequences.
- one approach is to convert the VH and VL sequences into full-length antibody genes by inserting them into expression vectors that already encode the heavy or light chain constant regions, such that the VH segment is linked to the one or more CH segment (s) within the vector is operatively linked, and also the VL segment is operatively linked to the CL segment within the vector.
- the recombinant expression vector may encode a signal peptide that facilitates secretion of the antibody chain from the host cell.
- the antibody chain gene can be cloned into the vector such that the signal peptide in reading frame is linked to the N-terminus of the antibody chain gene.
- the signal peptide may be an immunoglobulin signal peptide or a heterologous signal peptide (ie, a signal peptide from a non-immunogiobulin protein).
- the expression vectors of the invention may have regulatory sequences which control the expression of the genes for the antibody chain in a host cell.
- the term "regulatory sequence” is intended to include promoters, enhancers, and other expression control elements (eg, polyadenylation signals) that control the transcription or translation of the antibody chain genes.
- regulatory sequences are, for example, in Goeddel; Gene Expression Technology: Methods in Enzymology 185, Academic Press, San Diego, CA (1990 ).
- regulatory sequences for expression in mammalian host cells include viral Elements that lead to high protein expression in mammalian cells, such as promoters and / or enhancers derived from cytomegalovirus (CMV) (such as the CMV promoter / enhancer), simian virus 40 (SV40) (such as the SV40 promoter / enhancer). , Adenovirus (eg, the Adenovirus Major Late Promoter AdMLP) and Polyoma
- CMV cytomegalovirus
- SV40 simian virus 40
- Adenovirus eg, the Adenovirus Major Late Promoter AdMLP
- Polyoma For further description of viral regulatory elements and sequences thereof, see eg U.S. Patent No. 5,168,062 from Stinsky, U.S. Patent No. 4,510,245 by Bell et al. and U.S. Patent No. 4,968,615 Schaffner et al.
- the recombinant expression vectors of the invention may have additional sequences, such as sequences that regulate replication of the vector in host cells (eg, origins of replication) and selectable marker genes.
- the selectable marker genes facilitate the selection of host cells into which the vector has been introduced (see, eg U.S. Patent No. 4,399,216 . 4,634,665 and 5,179,017 , all by Axel et al .).
- Preferred selectable marker genes include the gene for dihydrofolate reductase (DHFR) (for use in dhfr - host cells with methotrexate selection / amplification) and the neo gene (for G418 selection).
- DHFR dihydrofolate reductase
- the expression vector (s) encoding the heavy and light chains are transfected into a host cell using standard techniques.
- the various forms of the term "transfection" are intended to cover a variety of techniques commonly used to introduce exogenous DNA into a prokaryotic or eukaryotic host cell, eg, electroporation, calcium phosphate precipitation, DEAE-dextran transfection, and the like.
- the antibodies of the invention While it is theoretically possible to express the antibodies of the invention in either prokaryotic or eukaryotic host cells, expression of the antibodies is preferred in eukaryotic cells, and particularly in mammalian host cells, since the likelihood that a correctly folded and immunologically active antibody will be assembled and secreted in such eukaryotic cells and in particular mammalian cells is higher than in prokaryotic cells. Prokaryotic expression of antibody genes has been reported to be ineffective for the production of high yields of active antibody ( Boss, MA and Wood, CR (1985) Immunology Today 6: 12-13 ).
- the antibodies When recombinant expression vectors encoding the antibody genes are introduced into mammalian host cells, the antibodies are produced by culturing the host cells until the antibody expresses in the host cells, or preferably the host cell Antibodies are secreted into the culture medium in which the host cells grow.
- the antibodies can be recovered from the culture medium using standardized methods for the purification of proteins.
- Host cells may also be used to produce portions of intact antibodies, such as Fab fragments or scFv molecules. Variations of the procedure described above are of course part of the invention. For example, it may be desirable to transfect a host cell with DNA encoding either the light chain or the heavy chain (but not both) of an antibody of the invention. If light or heavy chains are present which are not required for the binding of the antigen of interest, the DNA encoding either or both of such a light or heavy chain may be partially or completely removed by recombinant DNA technology. Molecules expressed by such truncated DNA molecules also belong to the antibodies of the invention.
- bifunctional antibodies may be prepared in which one heavy and one light chain are an antibody of the invention and the other heavy and light chains have specificity for any antigen other than the antigen of interest by subjecting an antibody of the invention to a second antibody by standard chemical methods cross-linked.
- a recombinant expression vector encoding both the heavy antibody chain and the light antibody chain is introduced into dhff-CHO cells by calcium phosphate-mediated transfection.
- the heavy and light antibody chain genes are each operably linked to CMV enhancer / AdMLP promoter regulatory elements to effect strong transcription of the genes.
- the recombinant expression vector also carries a DHFR gene with which CHO cells transfected with the vector can be selected by using methotrexate selection / amplification. The selected transformed host cells are cultured so that the heavy and light antibody chains are expressed, and intact antibody is recovered from the culture medium.
- a covalent fusion is generated by in vitro translation of synthetic mRNAs carrying at their 3 'end puromycin, a peptidyl acceptor antibiotic, between an mRNA and the peptide or protein that it encodes.
- a specific mRNA from a complex mixture of mRNAs may be enriched for the oligomer of the invention or a derivative thereof based on the properties of the encoded peptide or protein (eg antibody or portion thereof) such as the binding of the antibody or portion thereof become.
- Antibody or portion thereof-encoding nucleic acid sequences obtained from screening such benches can be expressed by recombinant means in the manner described above (eg, in mammalian host cells) and further subject to further affinity maturation by either mRNA peptide in subsequent rounds By introducing mutations into the originally selected sequence (s), or by using other methods of in vitro affinity maturation of recombinant antibodies in the manner described above.
- the antibodies of the invention may also be prepared using a combination of in vivo and in vitro approaches, such as methods in which first an oligomer of the invention or a derivative thereof is allowed to act on an antibody repertoire in vivo in a host animal in order to stimulate the production of oligomer or derivative binding antibodies, and then the further antibody selection and / or antibody maturation (ie optimization) is accomplished by one or more in vitro techniques.
- such a combined method may involve first immunizing a non-human animal (eg, a mouse, rat, rabbit, chicken, camelid, goat or transgenic version thereof or a chimeric mouse) with the oligomer or derivative thereof of the invention to one To stimulate antibody response to the antigen, and then to produce and screen a phage display antibody library using immunoglobulin sequences from lymphocytes stimulated in vivo by the action of the oligomer or derivative.
- the first step of this combined approach may be performed in the manner described above in the context of the in vivo approaches, while the second step of this approach may be performed in the manner described above in connection with the in vitro approaches.
- Preferred methods for hyperimmunization of non-human animals followed by in vitro screening of phage display banks prepared from the stimulated lymphocytes include those described by BioSite Inc., see, eg WO 98/47343 . WO 91/17271 .
- U.S. Patent No. 5,427,908 and U.S. Patent No. 5,580,717 are described.
- a combined method involves first obtaining a non-human animal (eg, a mouse, rat, rabbit, chicken, camelid, goat, or a knockout and / or transgenic version thereof, or a chimeric mouse) with a subject of the invention
- a non-human animal eg, a mouse, rat, rabbit, chicken, camelid, goat, or a knockout and / or transgenic version thereof, or a chimeric mouse
- Oligomer or derivative thereof is immunized to stimulate an antibody response against the oligomer or derivative thereof, and the lymphocytes producing the antibodies with the desired specificity are selected by screening (for example, hybridomas prepared from the immunized animals).
- the genes for the antibodies or single domain antibodies are isolated from the selected clones (by standard cloning methods, such as the reverse transcriptase polymerase chain reaction) and subjected to in vitro affinity maturation to thereby enhance the binding properties of the selected antibody or antibodies.
- the first step of this approach may be accomplished in the manner described above in the context of the in vivo approaches, while the second step of this approach may be accomplished in the manner described above in connection with the in vitro approaches, in particular by Methods for in vitro affinity maturation used, such as those described in WO 97/29131 and WO 00/56772 are described.
- the recombinant antibodies are generated from single isolated lymphocytes using a procedure known to those skilled in the art as Lymphocyte Antibody Selection (SLAM) methods
- SAM Lymphocyte Antibody Selection
- a non-human animal eg a mouse, rat, rabbit, chicken, camelid, goat, or a transgenic version thereof, or a chimeric mouse
- a non-human animal eg a mouse, rat, rabbit, chicken, camelid, goat, or a transgenic version thereof, or a chimeric mouse
- individual antibody-secreting cells are selected using an antigen-specific hemolytic plaque assay.
- the oligomer or derivative thereof, or structurally related molecules of interest can be coupled to sheep erythrocytes using a linker such as biotin, thereby allowing individual cells secreting antibodies of appropriate specificity to be identified using the hemolytic plaque assay.
- variable regions are recovered from the cells by reverse transcriptase PCR, and these variable regions can then be ligated in conjunction with appropriate immunoglobulin constant regions (eg, human constant regions ) in mammalian host cells such as COS or CHO cells.
- appropriate immunoglobulin constant regions eg, human constant regions
- the host cells transfected with the amplified immunoglobulin sequences derived from in vivo selected lymphocytes may then be subjected to further in vitro analysis and selection, for example by spreading the transfected cells to isolate cells expressing antibodies of the desired specificity.
- the amplified immunoglobulin sequences can be further manipulated in vitro.
- oligomer-specific antibodies obtainable by the above methods are as well the subject of the present invention as their use for the preparation of a medicament for the treatment of amyloid- ⁇ -associated dementia diseases or for the preparation of a composition for the diagnosis of amyloid- ⁇ -associated dementia diseases.
- the antibodies obtainable according to the invention also include monoclonal antibodies, in particular chimeric and humanized antibodies, and also oligomer-binding fragments thereof.
- the present invention relates to proteins and in particular antibodies which specifically bind to an oligomer or derivative thereof according to the invention, i. Antibody with specificity for an inventive oligomer or derivative thereof.
- the present invention also relates to parts of these proteins or antibodies, in particular antigen-binding parts thereof, i. Protein or antibody parts which bind an oligomer according to the invention or a derivative thereof.
- the antibody according to the invention is preferably selected such that it has a specific binding kinetics (eg high affinity, low dissociation, low off-rate, strong neutralizing activity) for the specific binding to oligomer or derivative thereof according to the invention.
- a specific binding kinetics eg high affinity, low dissociation, low off-rate, strong neutralizing activity
- proteins and in particular antibodies are preferred which bind the oligomer or derivative thereof with higher affinity than monomeric A ⁇ (1-42) protein and / or monomeric A ⁇ (1-40) protein.
- Affinity ratios of 10, 100 or 1000 are particularly preferred.
- antibodies of the invention so as to inhibit the activity, particularly the activity neutoxische, inventive oligomers or derivatives thereof having an IC 50 of 1 x 10 -6 M or less.
- Inhibition constants IC 50 of 1 x 10 -7 M or less, 1 x 10 -8 M or less, 1 x 10 9 M or less, 1 x 10 -10 M or less, or 1 x 10 -11 M or less are specified Order increasingly preferred.
- the antibodies are preferably isolated antibodies. In another aspect, the antibodies are neutralizing antibodies.
- the antibodies of the invention include monoclonal and recombinant antibodies. According to many embodiments, the antibody may include an amino acid sequence derived entirely from a single species, such as a human antibody or a mouse antibody. According to further embodiments, the antibody may be a chimeric antibody or a CDR graft antibody or another form of humanized antibody.
- antibody is intended to refer to immunoglobulin molecules formed from 4 polypeptide chains, two heavy (H) chains, and two light (L) chains.
- the chains are usually linked together by disulfide bonds.
- Each heavy chain is composed of a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region.
- the heavy chain constant region is made up of three domains CH1, CH2 and CH3 formed.
- Each light chain is composed of a light chain variable region (abbreviated herein as LCVR or VL) and a constant light chain region.
- the light chain constant region is formed from a domain CL.
- antibody portion refers to one or more fragments of an antibody having specificity for an oligomer or derivative thereof of the invention, wherein the fragment or fragments are still capable of the oligomer or derivative specifically bind to it. It has been shown that the antigen-binding function of an antibody can be detected by fragments of a complete antibody.
- binding fragments within the meaning of the term "antigen-binding portion" of an antibody include (i) a Fab fragment, ie a monovalent fragment composed of the VL, VH, CL and CH1 domains; (ii) an F (ab ') 2 fragment, ie a bivalent fragment, which contains two Fab fragments linked together in the hinge region via a disulfide bridge; (iii) an Fd fragment composed of the VH and CH1 domains; (iv) an Fv fragment composed of the FL and VH domains of a single arm of an antibody; (v) a dAb fragment ( Ward et al., (1989) Nature 341: 544-546 ) consisting of a VH domain or VH, CH1, CH2, DH3, or VH, CH2, CH3; and (vi) an isolated complementarity determining region (CDR).
- a Fab fragment ie a monovalent fragment composed of the VL, VH, CL and CH1 domains
- the two domains of the Fv fragment, VL and VH are encoded by separate genes, they can further be linked together with a synthetic linker using recombinant techniques, whereby they can be produced as a single protein chain, wherein the VL- and VH regions come together to form monovalent molecules (known as single-chain Fv (ScFv), see eg Bird et al. (1988) Science 242: 423-426 ; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85: 5879-5883 ).
- Single chain antibodies should also be covered by the term "antigen-binding portion" of an antibody.
- Other forms of single chain antibodies such as “diabodies” are also included.
- an antibody or antigen-binding portion thereof may be part of a larger immunoadhesive molecule formed by covalent or non-covalent association of the antibody or antibody portion with one or more other proteins or peptides.
- immunoadhesive molecules include the use of the streptavidin core region to produce a tetrameric scFv molecule ( Kipriyanov, SM, et al. (1995) Human Antibodies and Hybridomas 6: 93-101 ) and the use of a cysteine residue, a marker peptide and a C-terminal polyhistidine tag to make bivalent and biotinylated scFv molecules ( Kipriyanov, SM, et al. (1994) Mol.
- Antibody parts such as Fab and F (ab ') 2 fragments, can be made from whole antibodies using conventional techniques, such as digestion with papain or pepsin.
- antibodies, antibody parts and immunoadhesion molecules can be obtained using standard recombinant DNA techniques.
- An "isolated antibody having specificity for an oligomer or derivative thereof" according to the invention means an antibody having specificity for an oligomer or derivative thereof according to the invention which is substantially free of other antibodies with different antigen specificities, ie in particular an antibody which is free of antibodies, which specifically bind to other forms of the A ⁇ (1-42) protein as described above.
- neutralizing antibody means an antibody whose binding to a particular antigen results in the inhibition of the biological activity of the antigen. This inhibition of the biological activity of the antigen can be assessed by measuring one or more indicators of the biological activity of the antigen using a suitable in vitro or in vivo assay.
- the term "monoclonal antibody” means an antibody derived from a hybridoma (e.g., an antibody derived from a hybridoma) Hybridoma technology, as the standard Hybridommethodik after Kohler and Milstein, produced hybridoma is secreted).
- a hybridoma-derived antibody having specificity for an oligomer or derivative thereof according to the present invention is therefore referred to as a monoclonal antibody.
- recombinant antibody refers to antibodies produced, expressed, generated or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell; Antibodies isolated from a recombinant combinatorial antibody library; Antibody isolated from an animal (eg, a mouse) transgenic by human immunoglobulin genes (see, e.g. Taylor, LD, et al. (1992) Nucl. Acids Res. 20: 6287-6295 ); or antibodies which are produced, expressed, generated or isolated in any other manner in which certain immunoglobulin gene sequences (such as human immunoglobulin gene sequences) are assembled with other DNA sequences.
- Recombinant antibodies include, for example, chimeric, CDR graft and humanized antibodies.
- human antibody refers to antibodies whose variable and constant regions are human germline immunoglobulin sequences as described, for example, by Kabat et al. (please refer Kabat, et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242 ), correspond or derive from it.
- the human antibodies of the present invention may include amino acid residues that are not encoded by human germ-line immunoglobulin sequences (eg, mutations introduced by in vivo or by somatic mutation in vivo or by viral mutagenesis), for example, in the CDRs, and particularly in CDR3.
- Recombinant human antibodies of the invention have variable regions and may also include constant regions derived from human germ line immunoglobulin sequences (see Kabat, EA, et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242 ).
- such recombinant human antibodies are subjected to in vitro mutagenesis (or if an animal is transgenic through human Ig sequences, in vivo somatic mutagenesis) such that the amino acid sequences of the VH and VL regions are recombinant antibody Sequences, although related to or derived from human germ line VH and VL sequences, do not naturally exist within the human antibody germ line repertoire in vivo.
- such recombinant antibodies are the result of selective mutagenesis or reverse mutation, or both.
- reverse mutation refers to a method in which some or all of the somatic mutant amino acids of a human antibody are replaced with the corresponding germline residues of a homologous germline antibody sequence.
- the heavy and light chain sequences of a human antibody of the invention are separately compared to the germline sequences in the VBASE database to identify the most homologous sequences. Signs in the human antibody of the invention are attributed to the germline sequence by mutating at defined nucleotide positions encoding such aberrant amino acids.
- the direct or indirect significance of each amino acid for antigen binding thus identified as a candidate for reverse mutation should be examined, and an amino acid which, upon mutation, interferes with a desirable property of the human antibody should not be included in the final human antibody.
- those amino acid positions which differ from the closest germline sequence but are identical to the corresponding amino acid sequence of a second germline sequence can be kept unchanged, provided that the second germline sequence has the sequence of the human antibody according to the invention is identical and co-linear at least in 10 and preferably in 12 amino acids on both sides of the amino acid in question.
- Reverse mutations can be made at any stage of antibody optimization.
- chimeric antibody refers to antibodies that include heavy and light chain variable region sequences from a species, but in which the sequences of one or more of the CDR regions of VH and / or VL with CDR sequences of a are replaced by other species, such as antibodies, which have murine heavy and light chain variable regions in which one or more of the mouse CDRs (e.g., CDR3) are replaced with human CDR sequences.
- humanized antibody refers to antibodies that contain sequences of the heavy and light chain variable region from a non-human species (e.g., mouse, rat, rabbit, chicken, camelid, goat), but in which at least a portion of the art VH and / or VL sequence has been altered to be more "human-like", i. H. to be more similar to human germ line variable sequences.
- a non-human species e.g., mouse, rat, rabbit, chicken, camelid, goat
- VH and / or VL sequence has been altered to be more "human-like", i. H. to be more similar to human germ line variable sequences.
- One type of humanized antibody is a CDR graft antibody in which human CDR sequences are inserted into non-human VH and VL sequences to replace the corresponding non-human CDR sequences.
- surface plasmonresonance refers to an optical phenomenon that can be used to analyze biospecific interactions by detecting changes in protein concentrations with a biosensor matrix using, for example, the BlAcore system (Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, NJ ).
- BlAcore Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, NJ .
- K off refers to the off-rate constant for the dissociation of an antibody from the antibody / antigen complex.
- K d refers to the dissociation constant of a particular antibody-antigen interaction.
- the binding affinity of the antibodies of the invention can be assessed using standardized in vitro immunoassays, such as ELISA or BlAcore analyzes.
- compositions comprising a protein according to the invention and in particular a Antibodies according to the invention and optionally a pharmaceutically acceptable carrier.
- Pharmaceutical compositions according to the invention may further comprise at least one additional therapeutic agent, e.g. B. one or more additional therapeutic agents for the treatment of a disease, the alleviation of the antibodies of the invention are useful include.
- the pharmaceutical composition may further include one or more additional therapeutic agents useful for the treatment of diseases in which the activity of the oligomer is important.
- Pharmaceutically acceptable carriers include all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, as long as they are physiologically compatible.
- Pharmaceutically acceptable carriers include, for example, water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, and the like, as well as combinations thereof.
- isotonic agents for example, sugars, polyalcohols, such as mannitol or sorbitol, or sodium chloride.
- Pharmaceutically acceptable carriers may further include minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives or buffers which increase the shelf life or efficacy of the antibodies.
- the pharmaceutical compositions may be suitable for parenteral administration, for example.
- the antibodies are preferably prepared as injectable solutions with an antibody content of 0.1-250 mg / ml.
- the injectable solutions may be formulated in liquid or lyophilized form in a flint glass or vial, ampoule or filled syringe as a dosage form.
- the buffer may contain L-histidine (1-50 mM, preferably 5-10 mM) and have a pH of 5.0-7.0, preferably 6.0.
- Other suitable buffers include, but are not limited to, sodium succinate, sodium citrate, sodium phosphate or potassium phosphate buffer.
- Sodium chloride may be used to adjust the tonicity of the solution to a concentration of 0-300 mM (preferably 150 mM for a liquid dosage form).
- Cryoprotectants may be included for a lyophilized dosage form, eg, sucrose (eg 0-10%, preferably 0.5-1.0%). Other suitable cryoprotectants include trehalose and lactose.
- Fillers can be used for a lyophilized dosage form, for example mannitol (eg 1 - 10%, preferably 2 - 4%).
- Stabilizers can be used in both liquid and lyophilized dosage forms, eg L-methionine (eg 51-50 mM, preferably 5-10 mM).
- Suitable bulking agents include glycine and arginine.
- surfactants may be used, for example polysorbate-80 (eg 0-0.05%, preferably 0.005-0.01%).
- surfactants include polysorbate-20 and BRIJ surfactants.
- compositions of the invention can take a variety of forms. These include liquid, semi-solid and solid dosage forms such as liquid solutions (eg injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories.
- liquid solutions eg injectable and infusible solutions
- dispersions or suspensions tablets, pills, powders, liposomes and suppositories.
- the preferred form depends on the intended mode of administration and therapeutic application.
- compositions in the form of injectable or infusible solutions are preferred, for example, compositions that are similar to the passive immunization of humans with other antibodies.
- the preferred route of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular).
- the antibody is administered by intravenous infusion or injection.
- the antibody is administered by intramuscular or subcutaneous injection.
- compositions typically must be sterile and stable under the conditions of manufacture and storage.
- the compositions may be formulated as a solution, microemulsion, dispersion, liposome, or other ordered structure suitable for high drug concentrations.
- Sterile injectable solutions can be prepared by incorporating the active compound (ie antibody) in the required amount into a suitable solvent, optionally with one or a combination of the above ingredients as needed, and then sterile-filtering.
- Dispersions are typically prepared by incorporating the active compound in a sterile vehicle containing a base dispersion medium and optionally other ingredients needed.
- a sterile lyophilized powder for the preparation of sterile injectable solutions vacuum drying and spray drying are preferred methods of preparation by which a powder of the active ingredient and optionally other desirable ingredients are obtained from a previously sterile-filtered solution.
- the right Flowability of a solution can be maintained by, for example, using a coating such as lecithin, maintaining the required particle size in the case of dispersions, or using surfactants.
- Prolonged absorption of injectable compositions can be achieved by incorporating an agent which retards absorption, e.g., monostearate salts and gelatin, into the composition.
- the antibodies of the invention may be administered by a variety of methods known to those skilled in the art, although for many therapeutic applications, subcutaneous injection, intravenous injection or infusion is the preferred mode of administration.
- the person skilled in the art knows that the route and / or mode of administration depends on the desired result.
- the active compound may be formulated with a carrier that protects the compound against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems.
- a controlled release formulation including implants, transdermal patches, and microencapsulated delivery systems.
- Biodegradable biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid.
- the methods for preparing such formulations are well known to those skilled in the art, see, for example Sustained and Controlled Release Drug Delivery Systems, JR Robinson, ed., Marcel Dekker, Inc., New York, 1978 ,
- an antibody of the invention can be administered orally, for example in an inert diluent or an assimilable edible carrier.
- the antibody (and other ingredients if desired) may also be enclosed in a hard or soft gelatin capsule, compressed into tablets or added directly to the diet.
- the antibodies may be mixed with excipients and used in the form of swallowable tablets, buccal tablets, capsules, elixirs, suspensions, syrups and the like. If an antibody according to the invention is to be administered by a route other than the parenteral route, it may be necessary to choose a coating of a material which prevents its inactivation.
- the antibodies of the invention are preferably capable of neutralizing, both in vitro and in vivo, the activity of oligomers of the invention or derivatives thereof to which they bind.
- the antibodies can therefore inhibit activity Oligomers according to the invention or derivatives thereof are used, for.
- the subject matter of the invention is a method for inhibiting the activity of oligomers or derivatives thereof according to the invention, wherein an antibody according to the invention is allowed to act on an oligomer or derivative thereof in such a way that the activity of the oligomer or derivative thereof is inhibited.
- another aspect of the present invention relates to a method of inhibiting the activity of oligomers or derivatives thereof of the invention in a subject afflicted with a disease involving amyloid ⁇ -protein and, in particular, the activity of the oligomer or derivative thereof of the invention is.
- This method involves the administration of at least one antibody of the invention to the subject for the purpose of inhibiting the activity of the oligomer or derivative thereof to which or which the antibody binds.
- the individual is preferably a human.
- An antibody of the invention may be administered to a human subject for therapeutic purposes.
- an antibody of the invention may be administered to a non-human mammal for veterinary purposes or as part of an animal model for a particular disease. Such animal models may be useful to assess the therapeutic efficacy of antibodies of the invention (e.g., to test dosages and timing of administration).
- oligomers or derivatives thereof according to the invention play a role
- diseases in whose formation and / or course an oligomer or derivative thereof according to the invention is involved By this is meant in particular those diseases in which oligomers or derivatives thereof according to the invention are demonstrably or presumably responsible for the pathophysiology of the disease or constitute a factor contributing to the development and / or course of the disease. Accordingly these include those diseases in which the inhibition of the activity of oligomers or derivatives thereof according to the invention is able to alleviate symptoms and / or progression of the disease.
- the antibodies of the invention may be administered together with one or more additional therapeutic agents useful in the treatment of the diseases described above.
- compositions of the present invention will generally contain a therapeutically effective amount or a prophylactically effective amount of at least one antibody of the invention.
- dosage plans can be selected and adjusted. For example, one can administer a single dose, several separate doses over time or administer an increasing or decreasing dosage depending on the requirements of the therapeutic situation. It is particularly advantageous to formulate parenteral compositions in unit dosage form to facilitate administration and to ensure uniformity of dosage.
- the determination is made immunologically. In principle, this can be done with any analytical or diagnostic test method in which antibodies are used. These include agglutination and precipitation techniques, immunoassays, immunohistochemical methods, and immunoblot techniques, e.g. Western blotting or dot blotting. Also in vivo methods include, for example, imaging methods.
- immunoassays Both competitive immunoassays, i. Antigen and labeled antigen (tracer) compete for antibody binding, as well as sandwich immunoassays, i. the binding of specific antibodies to the antigen is detected with a second, mostly labeled antibody.
- sandwich immunoassays i. the binding of specific antibodies to the antigen is detected with a second, mostly labeled antibody.
- assays can be both homogeneous, i. without a solid and liquid phase separation, as well as being heterogeneous, i. bound labels are separated from unbound ones, for example via solid phase bound antibodies.
- the different heterogeneous and homogeneous immunoassay formats can be assigned to specific classes depending on the labeling and measuring method, for example RIAs (radioimmunoassays), ELISA (enzyme linked immunosorbent assay), FIA (fluorescence immunoassay), LIA (luminescence immunoassay), TRFIA (temporally resolved FIA), IMAC (immune activation), EMIT (enzyme multiplied immune test), TIA (turbidimetric immunoassay), I-PCR (immuno-PCR).
- RIAs radioimmunoassays
- ELISA enzyme linked immunosorbent assay
- FIA fluorescence immunoassay
- LIA luminescence immunoassay
- TRFIA temporary FIA
- IMAC immunoactivation
- EMIT enzyme multiplied immune test
- TIA turbidimetric immunoassay
- I-PCR immuno-PCR
- oligomer determination For the oligomer determination according to the invention, competitive immunoassays are preferred. Labeled oligomer (tracer) competes with the sample oligomer to be quantified for binding to the antibody used. From the amount of displaced tracer can be determined using a standard curve, the amount of antigen, that is, the amount of oligomer in the sample.
- enzymes have proven to be advantageous.
- systems based on peroxidases especially horseradish peroxidase, may be alkaline Phosphatase and the ß-D-galactosidase can be used.
- specific substrates are available whose implementation can be followed, for example, photometrically.
- Suitable substrate systems are based on p-nitrophenyl phosphate (p-NPP), 5-bromo-4-chloro-3-indolyl phosphate / nitroblue tetrazolium (BCIP / NPT), fast red / naphthol AS-TS phosphate for alkaline phosphatase; 2,2-azino-bis- (3-ethylbenzthiazoline-6-sulfonic acid) (ABTS), o-phenylenediamine (OPT), 3,3 ', 5,5'-tetramethylbenzidine (TMB), o-dianisidine, 5-aminosalicylic acid , 3-dimethylaminobenzoic acid (DMAB) and 3-methyl-2-benzothiazoline hydrazone (MBTH) for peroxidases; O-nitrophenyl- ⁇ -D-galactoside (o-NPG), p-nitrophenyl- ⁇ -D-galactoside and 4-methylumbeliphenyl- ⁇ -D
- Tracers used are labeled oligomers. In this sense, to determine a particular oligomer to mark the oligomer to be determined and use as a tracer.
- the coupling of labels to oligomers for the preparation of tracers can be done in a conventional manner.
- the above statements on the derivatization of oligomers according to the invention are referred to by analogy.
- a number of labels suitably modified for conjugation to proteins are available, for example, biotin, avidin, extravidin or streptavidin-conjugated enzymes, maleimide-activated enzymes, and the like.
- These labels can be reacted directly with the oligomer or, if necessary, with appropriately derivatized oligomer to form a tracer.
- a streptavidin-peroxidase conjugate this will first require biotinylation of the oligomer.
- the skilled person suitable methods are known.
- the antigen-antibody complex can be bound to the carrier for the purpose of separation, for example via an anti-idiotypic antibody coupled to the carrier, eg an antibody directed against rabbit IgG.
- Carriers in particular microtiter plates coated with appropriate antibodies, are known and in some cases commercially available.
- kits usually includes several containers for separate arrangement of components. All components may be provided in ready-to-use dilution, as a dilution concentrate or as a dry substance or lyophilizate to dissolve or suspend; any or all of the components may be frozen or stored at ambient temperature until use. Sera are preferably flash-frozen, for example at -20 ° C, so that in these cases an immunoassay prior to use is preferably to be maintained at freezing temperatures.
- immunoassay Other components attached to the immunoassay are based on the type of immunoassay. As a rule, standard protein, optionally required tracer and control serum are added together with the antiserum. Further, microtiter plates, preferably coated with antibody, may be added to buffers, for example for testing, washing or reaction of the substrate, and the enzyme substrate itself.
- substances which inhibit the aggregation of the oligomers according to the invention or accelerate their disaggregation are also of interest.
- Such substances are in particular possible therapeutics for the treatment of the above amyloid- ⁇ -associated diseases, such. B. Alzheimer's disease.
- This method can also be applied to mixtures of biological origin, e.g. Cell preparation and extracts to produce natural binding partners having affinity for the oligomers of the invention, e.g. Cell surface antigens, especially receptors, and soluble ligands, such as certain proteins and mediators to identify.
- biological origin e.g. Cell preparation and extracts
- natural binding partners having affinity for the oligomers of the invention, e.g. Cell surface antigens, especially receptors, and soluble ligands, such as certain proteins and mediators to identify.
- the present invention also relates to screening methods, ie both primary and secondary screening methods, in which preferably at least one of the methods described below is used. If several methods are used, this can be done with a time delay or simultaneously on one and the same sample or on different samples of a substance to be investigated.
- FlashPlateR FlashPlateR technology
- Kits and components for carrying out this assay may be obtained commercially, for example from NENR Life Science Products. This principle is also based on microtiter plates (96 or 384) coated with scintillant substance.
- the substances or parts of mixtures of substances identifiable by this method as a ligand binding to the oligomer, derivative thereof or at least one oligomer or derivative thereof containing a corresponding composition thereof are as well the subject of the present invention as their use for the manufacture of a medicament for the treatment of amyloid- ⁇ -associated, in particular dementielle illnesses or for the production of a composition for the diagnosis of amyloid-ß-associated, in particular dementielle illnesses.
- concentrations of oligomers of the invention are expressed in terms of mole of A ⁇ (1-42) monomeric polypeptide.
- ⁇ -amyloid (1-42) protein corresponds to the term amyloid ⁇ (1-42) protein.
- proteins (polypeptides) used are of human origin.
- Example 1a 60 ⁇ l of the stock solution from Example 1a are admixed with 690 ⁇ l PBS buffer (20 mM sodium phosphate, 140 mM NaCl, pH 7.4) and adjusted to a content of 0.2% with 75 ⁇ l 2% sodium dodecyl sulfate (SDS) solution. SDS set. It is then incubated for 5 hours at 37 ° C and centrifuged for 10 min at 10,000 g. This A ⁇ (1-42) oligomer A preparation (about 400 ⁇ M A ⁇ (1-42)) can be stored at -20 ° C.
- PBS buffer 20 mM sodium phosphate, 140 mM NaCl, pH 7.4
- SDS sodium dodecyl sulfate
- rat A ⁇ (1-42) oligomer A preparation (about 400 ⁇ M rat A ⁇ (1-42)) can be stored at -20 ° C.
- Example 1 a 60 .mu.l of the stock solution from Example 1 a are mixed with 690 ul PBS buffer (20 mM sodium phosphate, 140 mM NaCl, pH 7.4) and adjusted to a content of 0.5% lauric acid with 75 ul 5% lauric acid solution , It is then incubated for 5 hours at 37 ° C and centrifuged for 10 min at 10,000 g.
- This A ⁇ (1-42) oligomer A preparation (approximately 400 ⁇ M A ⁇ (1-42)) can be stored at -20 ° C.
- 60 ⁇ l of the stock solution from example 1a are admixed with 690 ⁇ l PBS buffer (20 mM sodium phosphate, 140 mM NaCl, pH 7.4) and 75 ⁇ l 5% lauroyl sarcosine solution to a content of 0.5% lauroyl sarcosine set. It is then incubated for 5 hours at 37 ° C and centrifuged for 10 min at 10,000 g.
- This A ⁇ (1-42) oligomer A preparation (approximately 400 ⁇ M A ⁇ (1-42)) can be stored at -20 ° C.
- ⁇ -amyloid (1-42) protein (abbreviated to A ⁇ (1-42); peptide-synthetic material, lyophilizate, Bachem, Germany) are taken up in 220 ⁇ l of 10 mM aqueous HCl solution and incubated for 10 minutes at room temperature incubated. Insoluble constituents are centrifuged off at 10,000 g, 5 min. The supernatant (1 mM A ⁇ (1-42)) contains the A ⁇ (1-42) protein and is processed as follows:
- hA ⁇ (1-42) oligomer A preparation 100 ⁇ M can be stored at -20 ° C.
- a ⁇ (1-42) protein (abbreviated to A ⁇ (1-42), peptide-synthetic material, lyophilizate, Bachem, Germany) are dissolved in 44 ⁇ l of 1% SDS / H 2 O (5 mM A ⁇ (1-42)). 5 ⁇ l of the solution are mixed with 40 ⁇ l PBS and 5 ⁇ l 2% SDS and incubated for 16 h at 37 ° C. Insoluble constituents are centrifuged off for 5 minutes at 10,000 g. The resulting A ⁇ (1-42) oligomer A preparation (500 ⁇ M A ⁇ (1-42)) can be stored at -20 ° C.
- rat ⁇ -amyloid (1-42) protein (abbreviated to rat A ⁇ (1-42); peptide-synthetic material, lyophilizate, Bachem, Germany) are dissolved in 44 ⁇ l of 1% SDS / H 2 O ( 5 mM rat A ⁇ (1-42)). 5 ⁇ l of the solution are mixed with 40 ⁇ l PBS and 5 ⁇ l 2% SDS and incubated for 16 h at 37 ° C. Insoluble constituents are centrifuged off for 5 minutes at 10,000 g. The rat A ⁇ (1-42) oligomer A preparation (500 ⁇ M rat A ⁇ (1-42)) thus obtained can be stored at -20 ° C.
- rat A ⁇ (1-42) protein abbreviated to rat A ⁇ (1-42); peptide-synthetic material, lyophilizate, Bachem, Germany
- 5 ⁇ l of the solution are mixed with 40 ⁇ l PBS and 5 ⁇ l 2% SDS and incubated for 16 h at 37 °
- An A ⁇ (1-42) oligomer A solution obtained according to Example 2a is diluted with 2.475 ml of water (0.05% SDS content, 0.1 mM A ⁇ (1-42)) and incubated at 37 ° C. for 20 hours , Aliquots of this A ⁇ (1-42) oligomer B preparation can be frozen at -80 ° C and stored for further study.
- a rat A ⁇ (1-42) oligomer A solution obtained according to Example 2b is diluted with 2.475 ml of water (0.05% SDS content, 0.1 mM rat A ⁇ (1-42)) and for 20 hours Incubated at 37 ° C. Aliquots of this rat A ⁇ (1-42) oligomer B preparation can be frozen at -80 ° C and stored for further study.
- An A ⁇ (1-42) oligomer A solution obtained according to Example 2c is diluted with 2.475 ml of water (0.125% lauric acid content, 0.1 mM A ⁇ (1-42)) and incubated at 37 ° C. for 20 hours. Aliquots of this A ⁇ (1-42) oligomer B preparation can be frozen at -80 ° C and stored for further study.
- An A ⁇ (1-42) oligomer B preparation prepared in accordance with Example 5a is admixed with 30 ml of PBS buffer containing 0.1% Pluronic® F68 (BASF) and precipitated in the Centriprep YM, 30 KD, Fa Amicon concentrated to 3 ml. Any residues are removed by centrifugation (5 min at 10,000 g). The supernatant is removed. Aliquots of this A ⁇ (1-42) oligomer B preparation can be frozen at -80 ° C and stored for further study.
- Pluronic® F68 BASF
- biotin- ⁇ -amyloid (1-42) protein (short: biotin-A ⁇ (1-42), peptide synthetic material, lyophilisate, AnaSpec) are dissolved in 200 ⁇ l 1,1,1,1,3,3 , 3-hexafluoro-2-propanol and incubated for 30 min at 37 ° C in an Eppendorf tube. It is then evaporated to dryness in a vacuum concentrator (Speed Vac). The residue is taken up in 20.5 ⁇ l of DMSO to give a 5 mM biotin-A ⁇ (1-42) strain suspension. This can be stored at -20 ° C.
- fluorescein- ⁇ -amyloid (1-42) protein short: fluorescein A ⁇ (1-42), peptide synthetic material, lyophilisate, AnaSpec
- fluorescein A ⁇ 1-42
- peptide synthetic material lyophilisate, AnaSpec
- a vacuum concentrator Speed Vac
- the residue is taken up with 20.5 ⁇ l of DMSO to give a 5 mM fluorescein-A ⁇ (1-42) strain suspension. This can be stored at -20 ° C.
- a fluorescein A ⁇ (1-42) oligomer A solution obtained according to Example 11 is diluted with 82 ⁇ l of water (0.05% SDS content, 0.1 mM A ⁇ (1-42)) and at 37 ° for 16 hours C incubated.
- the fluorescein A ⁇ (1-42) oligomer B preparation can be frozen at -80 ° C and stored for further studies ( Fig. 4 ).
- the evaluation reveals that the A ⁇ (1-42) oligomer B preparation is characterized by a major peak in the molecular weight region of about 50 kDa Having protein fraction. As under denaturing conditions in SDS-PAGE, this protein fraction differs significantly from the monomeric A ⁇ (1-42) protein characterized by a major peak in the molecular weight region of about 16 kDa.
- the evaluation reveals that the A ⁇ (1-42) oligomer B preparation with reduced SDS content has a protein fraction characterized by a major peak in the molecular weight range of about 100 kDa.
- the A ⁇ (1-42) oligomer B-CL preparation with reduced SDS content has a protein fraction characterized by a major peak in the molecular weight region of about 60 kDa.
- the detergent contained in the preparations is neutralized by the nonionic detergent Triton X-100.
- 1 .mu.l 4% Triton X-100
- 10 .mu.l are pipetted to 10 .mu.l of the preparation from Example 5a and incubated for 5 min at room temperature. Thereafter, 10 .mu.l are added with the same volume of native sample buffer (4 ml of 1M Tris, pH 6.8, 8 ml of glycerol, 1 ml bromophenol blue in 50 ml of H 2 O and electrophoresis (running buffer: 7.5 g of tris, 36 g of glycine to 2.5 l of H 2 O).
- molecular weights can also be assigned to the oligomers according to the invention, in particular to oligomers B, also in native molecular weight analysis methods such as gel permeation chromatography (see Example 17) or native gel electrophoresis (see Example 18).
- the A ⁇ (1-42) oligomers B obtained according to Example 6b are tested for stability in PBS buffer under the following conditions.
- the A ⁇ (1-42) oligomers B obtained according to Example 6b are diluted to 0.5 mg / ml with PBS buffer and incubated for 24 hours or 96 hours at room temperature or at 37 ° C. Subsequently, the band pattern was analyzed in an SDS-PAGE. The band pattern is identical in all samples.
- Aliquots of the A ⁇ (1-42) oligomer B preparation obtained according to Example 6b are diluted to 0.5 mg / ml with buffer (20 mM Na phosphate, 140 mM NaCl, pH 7.4) and incubated with the following conditions 1/50 of the weight of the in Fig. 9 protease solutions incubated for 20 h at 37 ° C and pH 7.4. 1 ⁇ g aliquots of the batches are then analyzed in an SDS-PAGE ( Fig. 9 ).
- a ⁇ (1-42) oligomers B have high plasma stability.
- the biological half-life in the plasma is therefore in the range of about 8 hours or longer.
- biotin A ⁇ (1-42) Binding of biotin A ⁇ (1-42) oligomers with molecular weights of 17 kDa and 22 kDa [biotin A ⁇ (1-42) oligomers A] and of 42 kDa and 52 kDa [biotin A ⁇ (1-42) - Oligomers B] to the surface of human neuronal cells
- the binding of human ⁇ -amyloid (1-42) protein and the two A ⁇ (1-42) oligomer A and A ⁇ (1-42) oligomer B preparations to the human neuroblastoma cell line IMR-32 is assayed by FACScan (Beckton Dickinson).
- a suspension of IMR-32 cells (1.5 x 10 6 cells / 0.1 ml PBS) is probed with biotin-labeled, human ⁇ -amyloid (1-42) protein (peptide synthetic material, lyophilisate, AnaSpec) and the Biotin-labeled oligomers A and B containing preparations (Example 8 or 9) for 20 minutes at 37 ° C incubated.
- the cells are washed with buffer (PBS plus 1% BSA) and incubated with Streptavidin isothiocyanate-coupled fluorescein (Sigma) for 20 minutes at room temperature. After a buffer wash, binding to the surface of IMR-32 cells was analyzed by FACScan. The broken line shows the background fluorescence in the absence of the biotin labeled components. The addition of the individual preparations resulted in a large increase in cell-associated fluorescence and is indicated by the thick line.
- the binding of the oligomers A ( Fig. 7B ) and B ( Fig. 7C ) to the cell surfaces differs significantly from the binding of the monomeric ⁇ -amyloid (1-42) protein ( Fig. 7A ). The data show specific binding sites for the oligomers on human cell surfaces.
- a calibration series of the A ⁇ (1-42) oligomer B preparation in PBS in the concentration range of 1.58 ng / ⁇ l-0.005 ng / ⁇ l is initially prepared.
- a homogenate from a control brain of an untreated rat is carried and similarly a calibration series of the A ⁇ (1-42) oligomer B preparation is prepared in this brain homogenate. Thereafter, the homogenates are centrifuged for 1 h at 100,000 g in the ultracentrifuge and the supernatants used for the subsequent analyzes.
- the content of A ⁇ (1-42) oligomer B in the positive control can first be determined quantitatively and then also in the brain sample of treated rats as follows determine.
- rats While no A ⁇ (1-42) (0.01 nmol / g) is detectable in the brain extracts of untreated rats, rats were approximately 0.4 nmol in the 15 min after treatment by comparing the staining intensity with the corresponding concentrations of the positive control / g A ⁇ (1-42) and in the 120 min after treatment killed rats according to the same method still about 0.2 nmol / g detectable. This results in a mean biological half-life of about 105 min for the exogenously applied A ⁇ (1-42) oligomers B.
- Anti A ⁇ (1-42) reactive bands occur only in the range 38/48 kDa, which corresponds to the apparent molecular weight of the A ⁇ (1-42) oligomers B, ie the oligomeric structure remains in vivo application even after 2 hours receive.
- the same concentrations in the brains of the 15-min rats (0.4 nmol / g) and the 120-min rats (0.2 nmol / g) can be compared by comparing the staining intensities with corresponding intensely stained bands of A ⁇ (1-42 ) Oligomers B in the positive control as in the dot blot method.
- the preparation and cultivation of murine cortical neurons is carried out as a mixed culture with glial cells based on the literature ( Choi et al. (1987) J. Neurosci. 7, 357-368 ). In embryos, on 14.-15. Development Day the cortices of the meninges and deeper brain areas mechanically freed. The cells are separated by incubation in a 0.05% trypsin solution at 37 ° C for 5-7 minutes followed by repeated pipetting through a reduced-aperture Pasteur pipette.
- the toxic effect of A ⁇ (1-42) oligomers B is examined.
- the cells are incubated for 15 minutes in brain cell buffer (120 mM NaCl, 5.4 mM KCl, 1.8 mM CaCl 2 , 15 mM glucose, 25 mM HEPES, pH 7.2).
- Control cells 1 are incubated at the same time with 300 ⁇ M L-glutamate in brain cell buffer.
- the stock solution of A ⁇ oligomers is diluted to various final concentrations with serum-free medium (Minimum Essential Medium with 0.8 mM glutamine, 20 mM glucose, 26 mM NaHCO 3 ) and incubated for 24 h.
- control cells 1 treated with L-glutamate are incubated in serum-free medium in parallel.
- Another group of cells (control cells 2) is treated only with brain cell buffer and serum-free medium.
- the cell culture supernatants are removed, the remaining cells are destroyed by incubation in distilled water for 20 minutes, and the activity of the enzyme lactate dehydrogenase (LDH) in both solutions is determined enzymatically.
- LDH lactate dehydrogenase
- control cells 1 Of the Mean value in the glutamate-treated cells (control cells 1) is equated with 100% neuronal death, the mean of the cells treated with neither L-glutamate nor A ⁇ oligomers (control cells 2), with 0% neuronal death and the values of converted accordingly with Aß oligomers treated cells.
- the mean value of the neurotoxicity of all determinations at the respective concentrations used shows a marked toxic effect of the A ⁇ (1-42) oligomers with molecular weights of 38 kDa and 48 kDa [A ⁇ (1-42) oligomer B], cf. Fig. 8 ,
- the adjuvant is mixed with a solution of the antigen in the ratio of 2: 1 until a stable emulsion is obtained.
- the emulsion is injected and forms a depot from which the antigen is released continuously.
- the antisera are obtained from the rabbit blood by standing at room temperature and then centrifuging at room temperature.
- the serum thus obtained is called serum (a1).
- a ⁇ (20-42) oligomer B preparation from Example 15a of LPH are coupled with glutaric dialdehyde under standard conditions and 2 additional rabbits are immunized according to the standard protocol with this conjugated A ⁇ (20-42) oligomer B: 1 day
- the antisera are obtained from the rabbit blood by standing at room temperature and then centrifuging at room temperature.
- the serum thus obtained is called serum (a2).
- the antisera are obtained from the rabbit blood by standing at room temperature and then centrifuging at room temperature.
- the serum thus obtained is called serum (b1).
- a ⁇ (12-42) oligomer B preparation from Example 15b are coupled to LPH with glutaric dialdehyde under standard conditions and 2 additional rabbits are immunized according to the standard protocol with this conjugated A ⁇ (12-42) oligomer B: 1 day
- the antisera are obtained from the rabbit blood by standing at room temperature and then centrifuging at room temperature.
- the serum thus obtained is called serum (b2).
- Example 14a 2 rabbits are immunized according to the standard protocol with unconjugated A ⁇ (1-42) oligomer B-CL preparation of Example 14a: 1 day Initial immunization and withdrawal of the preimmune serum 7th day 1. Boost 14th day 2. boost 28th day 3. Boost and bleeding 35th day blood collection
- the antisera are obtained from the rabbit blood by standing at room temperature and then centrifuging at room temperature.
- the serum thus obtained is called serum (c1).
- the antisera are obtained from the rabbit blood by standing at room temperature and then centrifuging at room temperature.
- the serum thus obtained is called serum (d1).
- a ⁇ (1-42) oligomer B preparation from Example 6b are coupled to LPH, with glutaric dialdehyde under standard conditions and 2 additional rabbits are immunized according to the standard protocol with this conjugated A ⁇ (1-42) oligomer B preparation: 1 day Initial immunization and withdrawal of the preimmune serum 7th day 1. Boost 14th day 2. boost 28th day 3. Boost and bleeding 35th day blood collection
- the antisera are obtained from the rabbit blood by standing at room temperature and then centrifuging at room temperature.
- the serum thus obtained is called serum (d2).
- the numbers indicate the minimum amount of antigen visible in [pmol; except for APP in each case based on monomer] (detection limit).
- the antibodies directed against these oligomers are comparable in strength to other forms such as fibrils, APP, and monomer, as with the A ⁇ (1-42) oligomers B (see Row 1) ) cross-react.
- These antibodies show an immune response comparable to mMAb 6E10 (Signet) and do not bind to oligomer-specific structures.
- mice were immunized with A ⁇ (1-42) oligomers from Example 6b and monoclonal antibodies were established in a manner known per se. Two out of ten Hybrdidoma secrete monoclonal antibodies whose binding profiles are similar to those of the antiserum (a1), especially with respect to the reactivities tested above.
- a ⁇ (1-42) solution in 0.1% NH 4 OH are diluted to 0.5 mg / ml with 300 ⁇ l buffer (20 mM Na phosphate, 140 mM NaCl, pH 7.4) and 0, 1 M HCL adjusted to pH 7.4 (100 ⁇ M A ⁇ (1-42)).
- the sample is incubated for 24 h at 37 ° C and then centrifuged for 10 min at 10,000 g.
- the protein residue obtained is resuspended with 400 ⁇ l of buffer (20 mM Na phosphate, 140 mM NaCl, pH 7.4).
- the A ⁇ (1-42) fibril preparation thus obtained can be stored at -20 ° C and used for further studies.
- FIG. 14 shows that the washing in of A ⁇ (1-42) oligomers suppresses the long-term potentiation in the hippocampus, especially in the "maintenance phase". Accordingly, the A ⁇ (1-42) oligomers B-CL have an influence on the information storage of nerve cells (cellular memory).
- the binding of rat A ⁇ (1-42) oligomers B from Example 5b to primary rat hippocampal neurons was examined.
- the hippocampal neurons were cultured in neurobasal medium supplemented with B27 on poly-L-lysine coated coverslips and used on day 14 of culture.
- the binding of the oligomers to the cell membrane of the neurons was carried out by adding 200 nM (total monomeric A ⁇ concentration) oligomers in fresh culture medium and incubating for 15 min. at 37 ° C. After removal of the A ⁇ -containing medium was washed twice with medium and the cells then fixed in 3.7% formaldehyde. After further washing of the cells, nonspecific binding sites were blocked with 10% normal donkey serum in PBS buffer for 90 min at room temperature.
- the 1st antibody 6E10 (from mouse) was applied at a dilution of 1: 2000 for 2 h at room temperature.
- the cells were washed again and incubated with the second antibody (from donkey), which is directed against mouse and to which the fluorescent dye Cy3 is coupled, for 2 h at room temperature.
- the coverslips with the neurons were fixed on a microscope slide with mounting medium.
- the hippocampal neurons with bound A ⁇ oligomers were displayed in a fluorescence microscope.
- an approach was used in which the 1st antibody 6E10 was omitted. This control thus shows the non-specific fluorescence, which is not based on A ⁇ .
- Fig. 15a As can be seen, the oligomers bind to the cell surface of the neurons in a punctured fashion. In contrast, the control without the first antibody 6E10 shows only a slight unspecific fluorescence by binding of the second antibody to the neurons ( Fig. 15b ).
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Immunology (AREA)
- Biomedical Technology (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Neurology (AREA)
- Genetics & Genomics (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Neurosurgery (AREA)
- Hematology (AREA)
- Urology & Nephrology (AREA)
- Microbiology (AREA)
- Epidemiology (AREA)
- Toxicology (AREA)
- General Physics & Mathematics (AREA)
- Physics & Mathematics (AREA)
- Biotechnology (AREA)
- Cell Biology (AREA)
- Pathology (AREA)
- Analytical Chemistry (AREA)
- Food Science & Technology (AREA)
- Mycology (AREA)
- Marine Sciences & Fisheries (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE10303974A DE10303974A1 (de) | 2003-01-31 | 2003-01-31 | Amyloid-β(1-42)-Oligomere, Verfahren zu deren Herstellung und deren Verwendung |
EP04707201.2A EP1594891B1 (fr) | 2003-01-31 | 2004-02-02 | Oligomeres de beta(1-42) amyloides, derives de ces composes et anticorps destines a ceux-ci, procede de fabrication et utilisation de ces composes |
Related Parent Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP04707201.2 Division | 2004-02-02 | ||
EP04707201.2A Division-Into EP1594891B1 (fr) | 2003-01-31 | 2004-02-02 | Oligomeres de beta(1-42) amyloides, derives de ces composes et anticorps destines a ceux-ci, procede de fabrication et utilisation de ces composes |
EP04707201.2A Division EP1594891B1 (fr) | 2003-01-31 | 2004-02-02 | Oligomeres de beta(1-42) amyloides, derives de ces composes et anticorps destines a ceux-ci, procede de fabrication et utilisation de ces composes |
Publications (3)
Publication Number | Publication Date |
---|---|
EP2336161A2 true EP2336161A2 (fr) | 2011-06-22 |
EP2336161A3 EP2336161A3 (fr) | 2012-03-07 |
EP2336161B1 EP2336161B1 (fr) | 2017-12-27 |
Family
ID=32667945
Family Applications (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP10179281.0A Expired - Lifetime EP2336161B1 (fr) | 2003-01-31 | 2004-02-02 | Oligomères de beta(1-42 amyloïdes, dérivés de ceux-ci et anticorps destinés à ceux-ci, procédé de fabrication et utilisation de ces composés |
EP04707201.2A Expired - Lifetime EP1594891B1 (fr) | 2003-01-31 | 2004-02-02 | Oligomeres de beta(1-42) amyloides, derives de ces composes et anticorps destines a ceux-ci, procede de fabrication et utilisation de ces composes |
EP10179255A Withdrawn EP2336160A3 (fr) | 2003-01-31 | 2004-02-02 | Oligomères de beta(1-42 amyloïdes, dérivés de ceux-ci et anticorps destinés à ceux-ci, procédé de fabrication et utilisation de ces composés |
EP10179297A Withdrawn EP2336159A3 (fr) | 2003-01-31 | 2004-02-02 | Oligomères de beta(1-42 amyloïdes, dérivés de ceux-ci et anticorps destinés à ceux-ci, procédé de fabrication et utilisation de ces composés |
Family Applications After (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP04707201.2A Expired - Lifetime EP1594891B1 (fr) | 2003-01-31 | 2004-02-02 | Oligomeres de beta(1-42) amyloides, derives de ces composes et anticorps destines a ceux-ci, procede de fabrication et utilisation de ces composes |
EP10179255A Withdrawn EP2336160A3 (fr) | 2003-01-31 | 2004-02-02 | Oligomères de beta(1-42 amyloïdes, dérivés de ceux-ci et anticorps destinés à ceux-ci, procédé de fabrication et utilisation de ces composés |
EP10179297A Withdrawn EP2336159A3 (fr) | 2003-01-31 | 2004-02-02 | Oligomères de beta(1-42 amyloïdes, dérivés de ceux-ci et anticorps destinés à ceux-ci, procédé de fabrication et utilisation de ces composés |
Country Status (15)
Country | Link |
---|---|
US (4) | US7902328B2 (fr) |
EP (4) | EP2336161B1 (fr) |
JP (4) | JP5150097B2 (fr) |
KR (3) | KR20090019911A (fr) |
CN (3) | CN101985036B (fr) |
AU (2) | AU2004207075B2 (fr) |
BR (1) | BRPI0407084A (fr) |
CA (2) | CA2514582C (fr) |
DE (1) | DE10303974A1 (fr) |
ES (1) | ES2567437T3 (fr) |
IL (3) | IL197312A0 (fr) |
MX (1) | MXPA05007964A (fr) |
NZ (2) | NZ541453A (fr) |
WO (1) | WO2004067561A1 (fr) |
ZA (1) | ZA200506934B (fr) |
Families Citing this family (89)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002003911A2 (fr) * | 2000-07-07 | 2002-01-17 | Lars Lannfelt | Prevention et traitement de la maladie d'alzheimer |
DE10259382A1 (de) * | 2002-12-18 | 2004-07-01 | Abbott Gmbh & Co. Kg | 3-Substituierte 3,4-Dihydro-thieno[2,3-d]pyrimidin-4-on-Derivate, ihre Herstellung und Verwendung |
DE10303974A1 (de) * | 2003-01-31 | 2004-08-05 | Abbott Gmbh & Co. Kg | Amyloid-β(1-42)-Oligomere, Verfahren zu deren Herstellung und deren Verwendung |
US7732162B2 (en) | 2003-05-05 | 2010-06-08 | Probiodrug Ag | Inhibitors of glutaminyl cyclase for treating neurodegenerative diseases |
US8250823B2 (en) | 2003-08-26 | 2012-08-28 | Ejot Gmbh & Co. Kg | Dowels and methods for the assembly of insulating panels |
SE0401601D0 (sv) * | 2004-06-21 | 2004-06-21 | Bioarctic Neuroscience Ab | Protofibril specific antibodies and uses thereof |
SG190665A1 (en) | 2004-07-30 | 2013-06-28 | Rinat Neuroscience Corp | Antibodies directed against amyloid-beta peptide and methods using same |
EP1787998A4 (fr) * | 2004-08-11 | 2008-08-27 | Mitsubishi Chem Corp | Anticorps et utilisation s'y rapportant |
EP1861422B1 (fr) * | 2005-03-05 | 2010-02-24 | Abbott GmbH & Co. KG | Methode de criblage, procede servant a purifier des a-beta oligomeres non diffusibles, anticorps selectifs contre les dits a-beta oligomeres non diffusibles et procede servant a preparer ces anticorps |
TW200700432A (en) * | 2005-03-05 | 2007-01-01 | Abbott Gmbh & Co Kg | Screening method, process for purifying of non-diffusible a β oligomers, selective antibodies against said non-diffusible a β oligomers and a process for manufacturing of said antibodies |
DE102005014936A1 (de) | 2005-03-24 | 2006-12-14 | Abbott Gmbh & Co. Kg | Substituierte Oxindol-Derivate, diese enthaltende Arzneimittel und deren Verwendung |
MY148086A (en) | 2005-04-29 | 2013-02-28 | Rinat Neuroscience Corp | Antibodies directed against amyloid-beta peptide and methods using same |
TW200726774A (en) * | 2005-06-30 | 2007-07-16 | Merck & Co Inc | Composition and method for producing stable amyloid beta oligomers |
JP2009510002A (ja) | 2005-09-30 | 2009-03-12 | アボット ゲゼルシャフト ミット ベシュレンクテル ハフツング ウント コンパニー コマンディトゲゼルシャフト | 反発誘導分子(rgm)タンパク質ファミリーのタンパク質の結合ドメイン、及びその機能的断片、及びそれらの使用 |
PL2289909T3 (pl) | 2005-11-30 | 2015-04-30 | Abbvie Inc | Sposób przeszukiwania, proces oczyszczania niedyfundujących oligomerów Abeta, selektywne przeciwciała przeciw niedyfundującym oligomerom Abeta i sposób wytwarzania tych przeciwciał |
JP2009518010A (ja) * | 2005-11-30 | 2009-05-07 | アボット・ラボラトリーズ | ヒトβアミロイドタンパク質の組み換え形態の調製方法及びこれらのタンパク質の使用 |
CN102898519B (zh) * | 2005-11-30 | 2015-10-28 | Abbvie公司 | 抗淀粉样β蛋白的单克隆抗体及其用途 |
SI2289909T1 (sl) * | 2005-11-30 | 2015-03-31 | Abbvie Inc. | Presejalni postopek, postopek za čiščenje nedifuzibilnih Abeta-oligomerov, selektivna protitelesa proti nedifuzibilnim Abeta-oligomerom in postopek za izdelavo protiteles |
AU2013200177B2 (en) * | 2005-11-30 | 2014-10-02 | Abbvie Deutschland Gmbh & Co Kg | Monoclonal antibodies against amyloid beta protein and uses thereof |
RS52004B (en) * | 2005-12-12 | 2012-04-30 | F. Hoffmann-La Roche Ag | ANTIBODIES AGAINST AMYLOID BETA WITH GLYCOSILATION IN THE VARIABLE REGION |
KR101505201B1 (ko) | 2005-12-12 | 2015-03-24 | 에이씨 이뮨 에스.에이. | 치료적 특성을 갖는 베타 1-42 특이적인 단일클론성 항체 |
EP2325209A3 (fr) * | 2006-03-23 | 2011-08-03 | BioArtic Neuroscience AB | Anticorps améliorés sélectifs de protofibrilles et leur utilisation |
CL2007002070A1 (es) * | 2006-07-14 | 2008-02-08 | Ac Immune S A Genentech Inc | Anticuerpo quimerico o humanizado, o fragmentos de ellos, que se adhieren especificamente a por lo menos un epitopo en la proteina beta-amiloide; molecula de acido nucleico que lo codifica; composicion que lo comprende; su uso para tratar enfermedade |
ATE426174T1 (de) * | 2006-07-28 | 2009-04-15 | Vista Ventures Gmbh | Verfahren zum nachweis der amyloid-beta oligomere in kírperflussigkeiten |
US8188046B2 (en) | 2006-10-16 | 2012-05-29 | University Of South Florida | Amyloid beta peptides and methods of use |
US8455626B2 (en) * | 2006-11-30 | 2013-06-04 | Abbott Laboratories | Aβ conformer selective anti-aβ globulomer monoclonal antibodies |
AU2008204335B2 (en) | 2007-01-11 | 2013-06-13 | Michael Bacher | Diagnosis and treatment of Alzheimer's and other neurodementing diseases |
EP2125015A1 (fr) * | 2007-02-27 | 2009-12-02 | Abbott GmbH & Co. KG | Méthode de traitement d'amyloïdoses |
US20100311767A1 (en) * | 2007-02-27 | 2010-12-09 | Abbott Gmbh & Co. Kg | Method for the treatment of amyloidoses |
ZA200905537B (en) | 2007-03-01 | 2010-10-27 | Probiodrug Ag | New use of glutaminyl cyclase inhibitors |
US7618944B2 (en) * | 2007-03-01 | 2009-11-17 | Intezyne Technologies, Inc. | Encapsulated amyloid-beta peptides |
EP2142514B1 (fr) | 2007-04-18 | 2014-12-24 | Probiodrug AG | Dérivés de thio-urée utilisés comme inhibiteurs de la glutaminyl cyclase |
US8613923B2 (en) | 2007-06-12 | 2013-12-24 | Ac Immune S.A. | Monoclonal antibody |
EP2574345A1 (fr) * | 2007-06-12 | 2013-04-03 | AC Immune S.A. | Anticorps humanisés à amyloïde bêta |
NZ601843A (en) * | 2007-06-12 | 2014-01-31 | Ac Immune Sa | Monoclonal anti beta amyloid antibody |
US8048420B2 (en) * | 2007-06-12 | 2011-11-01 | Ac Immune S.A. | Monoclonal antibody |
EP2650308A3 (fr) * | 2007-10-05 | 2014-11-12 | Genentech, Inc. | Utilisation d'anticorps anti-beta amyloide aux maladies oculaires |
BRPI0818621A8 (pt) * | 2007-10-05 | 2018-01-30 | Ac Immune Sa | composição farmacêutica, e, métodos para reduzir a carga da placa e a quantidade de placas na camada de célula de gânglio retinal de um indivíduo, para prevenir, tratar e/ou aliviar os efeitos de uma doença ocular, para diagnosticar uma doença ocular e uma predisposição a uma doença ocular, para monitorar doença ocular, para predizer responsividade de um paciente, e para reter ou diminuir pressão ocular nos olhos de um indivíduo |
WO2009048539A2 (fr) | 2007-10-05 | 2009-04-16 | Genentech, Inc. | Anticorps monoclonal |
KR20100115340A (ko) * | 2007-10-19 | 2010-10-27 | 이무나스 파마 가부시키가이샤 | Aβ 올리고머에 특이적으로 결합하는 항체 및 그의 이용 |
UA103602C2 (ru) * | 2007-10-29 | 2013-11-11 | Енсерм (Енстітю Насьональ Де Ля Санте Е Де Ля Решер Медікалє) | АНТИТЕЛО, СПЕЦИФИЧНОЕ К β-АМИЛОИДНЫМ ПЕПТИДАМ, И ЕГО ПРИМЕНЕНИЕ В КАЧЕСТВЕ ДИАГНОСТИЧЕСКОГО ИЛИ ЛЕКАРСТВЕННОГО СРЕДСТВА |
CA2707309A1 (fr) | 2007-12-18 | 2009-06-25 | Acumen Pharmaceuticals, Inc. | Nouveaux polypeptides du recepteur de l'addl, polynucleotides et cellules hotes pour une production recombinante |
EP3121277B1 (fr) | 2008-02-08 | 2018-04-11 | Immunas Pharma, Inc. | Anticorps pouvant se lier spécifiquement à ab-oligomère et son utilisation |
US20090239888A1 (en) * | 2008-02-12 | 2009-09-24 | Wisconsin Alumni Research Foundation | Methods for Inhibiting Amyloid Precursor Protein and Beta-Amyloid Production and Accumulation |
US8962803B2 (en) | 2008-02-29 | 2015-02-24 | AbbVie Deutschland GmbH & Co. KG | Antibodies against the RGM A protein and uses thereof |
CN102065881B (zh) | 2008-04-14 | 2014-03-12 | 埃尔奇诺瓦公司 | 稳定的淀粉样beta单体和寡聚体 |
WO2010011947A2 (fr) * | 2008-07-25 | 2010-01-28 | Abbott Laboratories | Analogues du peptide ss-amyloïde, oligomères de celui-ci, procédés de préparation et compositions comprenant lesdits analogues ou oligomères, et leurs utilisations |
US20100173828A1 (en) * | 2008-07-25 | 2010-07-08 | Abbott Gmbh & Co. Kg | Aß(X - 38 .. 43) oligomers, and processes, compositions, and uses thereof |
US9085614B2 (en) | 2008-08-01 | 2015-07-21 | Immunas Pharma, Inc. | Antibodies that specifically bind to Aβ oligomers and uses thereof |
US8283162B2 (en) | 2009-03-10 | 2012-10-09 | Abbott Laboratories | Antibodies relating to PIVKAII and uses thereof |
EP2419447B1 (fr) | 2009-04-17 | 2017-08-23 | Immunas Pharma, Inc. | Anticorps qui se lient spécifiquement aux oligomères a bêta et leur utilisation |
EP2258398A1 (fr) | 2009-05-26 | 2010-12-08 | Araclón Biotech, S. L. | Conjugués d'albumine-peptide d'amyloide et leurs utilisations |
EP2273273A1 (fr) | 2009-07-11 | 2011-01-12 | Rheinische Friedrich-Wilhelms-Universität Bonn | Inhibiteurs de la nitration de peptides ß amyloïdes et leurs utilisations pour le diagnostic et le traitement de la maladie d'Alzheimer |
ES2624835T3 (es) | 2009-08-06 | 2017-07-17 | Immunas Pharma, Inc. | Anticuerpos que se unen específicamente a los oligómeros A beta y uso de los mismos |
WO2011016239A1 (fr) | 2009-08-06 | 2011-02-10 | Immunas Pharma, Inc. | Anticorps qui se lient spécifiquement à des oligomères bêta a et utilisation de ceux-ci |
US8501420B2 (en) | 2009-08-31 | 2013-08-06 | Abbott Laboratories | Biomarkers for prediction of major adverse cardiac events and uses thereof |
ES2548913T3 (es) | 2009-09-11 | 2015-10-21 | Probiodrug Ag | Derivados heterocíclicos como inhibidores de glutaminil ciclasa |
CA2780069C (fr) | 2009-12-08 | 2018-07-17 | Abbott Gmbh & Co. Kg | Anticorps monoclonaux contre la proteine rgm a destines a etre utilises dans le traitement de la degenerescence de la couche de fibres nerveuses retiniennes |
JP6026284B2 (ja) | 2010-03-03 | 2016-11-16 | プロビオドルグ エージー | グルタミニルシクラーゼの阻害剤 |
JP5688745B2 (ja) | 2010-03-10 | 2015-03-25 | プロビオドルグ エージー | グルタミニルシクラーゼ(qc、ec2.3.2.5)の複素環阻害剤 |
EP2558494B1 (fr) | 2010-04-15 | 2018-05-23 | AbbVie Inc. | Protéines de liaison à la bêta amyloïde |
WO2011131748A2 (fr) | 2010-04-21 | 2011-10-27 | Probiodrug Ag | Nouveaux inhibiteurs |
US9320793B2 (en) * | 2010-07-14 | 2016-04-26 | Acumen Pharmaceuticals, Inc. | Method for treating a disease associated with soluble, oligomeric species of amyloid beta 1-42 |
US9120862B2 (en) | 2010-07-26 | 2015-09-01 | Abbott Laboratories | Antibodies relating to PIVKA-II and uses thereof |
NZ606357A (en) | 2010-07-30 | 2015-05-29 | Genentech Inc | Safe and functional humanized anti beta-amyloid antibody |
US9062101B2 (en) | 2010-08-14 | 2015-06-23 | AbbVie Deutschland GmbH & Co. KG | Amyloid-beta binding proteins |
WO2012123563A1 (fr) | 2011-03-16 | 2012-09-20 | Probiodrug Ag | Dérivés de benzimidazole en tant qu'inhibiteurs de la glutaminyl cyclase |
US8906382B2 (en) * | 2011-07-19 | 2014-12-09 | New York University | Method for treating amyloid disease |
US9926353B2 (en) | 2011-07-19 | 2018-03-27 | New York University | Immunotherapeutic modulation of amyloidogenic disease using non-fibrillogenic, non-amyloidogenic polymerized proteins and peptides |
MY194587A (en) | 2012-01-27 | 2022-12-05 | Abbvie Inc | Composition and method for the diagnosis and treatment of diseases associated with neurite degeneration |
JP2015511014A (ja) * | 2012-03-13 | 2015-04-13 | ヤンセン アルツハイマー イミュノセラピー | アルツハイマー病の診断、予後および監視におけるオリゴマー型Aβ |
CN104380111B (zh) * | 2012-04-05 | 2017-08-29 | 于利希研究中心有限公司 | 包含多价结合淀粉样β蛋白的D‑肽的聚合物及其应用 |
DK3498692T3 (da) | 2014-01-31 | 2022-05-16 | Cognition Therapeutics Inc | Isoindolin-sammensætninger og fremgangsmåder til behandling af neurodegenerativ sygdom og makulær degeneration |
MX2017000378A (es) | 2014-07-10 | 2017-08-25 | Bioarctic Neuroscience Ab | ANTICUERPOS DE UNION A PROTOFIBRILLAS BETA AMILOIDE (Aß) MEJORADOS. |
US20180050084A1 (en) * | 2015-02-27 | 2018-02-22 | Board Of Regents, The University Of Texas System | Polypeptide therapeutics and uses thereof |
IL302486A (en) | 2015-06-24 | 2023-06-01 | Hoffmann La Roche | Antibodies against the transnephrine receptor with adapted affinity |
JP6832283B2 (ja) | 2015-09-29 | 2021-02-24 | 浜松ホトニクス株式会社 | アミロイドβオリゴマーの検出方法、アミロイドβオリゴマー検出装置及びアミロイドβオリゴマー検出プログラム |
AR106189A1 (es) | 2015-10-02 | 2017-12-20 | Hoffmann La Roche | ANTICUERPOS BIESPECÍFICOS CONTRA EL A-b HUMANO Y EL RECEPTOR DE TRANSFERRINA HUMANO Y MÉTODOS DE USO |
MX2018003822A (es) | 2015-10-02 | 2018-06-22 | Hoffmann La Roche | Anticuerpos biespecificos contra el cd20 humano y el receptor de transferrina humano y metodos de uso. |
EP3461819B1 (fr) | 2017-09-29 | 2020-05-27 | Probiodrug AG | Inhibiteurs de la glutaminyl-cyclase |
DE102017130356A1 (de) * | 2017-12-18 | 2019-06-19 | Georg-August-Universität Göttingen Stiftung Öffentlichen Rechts, Universitätsmedizin | Verfahren zur Auftrennung verschiedener Abeta-Peptide durch Gelelektrophorese |
US11905336B2 (en) | 2018-09-10 | 2024-02-20 | Lung Therapeutics, Inc. | Modified peptide fragments of CAV-1 protein and the use thereof in the treatment of fibrosis |
CN110412294B9 (zh) * | 2019-08-07 | 2023-05-26 | 深圳市新产业生物医学工程股份有限公司 | 蛋白稳定液、蛋白校准品、试剂盒及检测蛋白校准品稳定性的方法 |
CN113308439B (zh) * | 2020-11-06 | 2023-05-05 | 华中科技大学 | 分泌人淀粉样蛋白-β单克隆抗体的杂交瘤细胞株及其应用 |
TW202300517A (zh) | 2021-03-12 | 2023-01-01 | 美商美國禮來大藥廠 | 抗類澱粉β抗體及其用途 |
WO2022251048A1 (fr) | 2021-05-24 | 2022-12-01 | Eli Lilly And Company | Anticorps anti-amyloïde bêta et leurs utilisations |
WO2023107830A1 (fr) * | 2021-12-06 | 2023-06-15 | The Board Of Trustees Of The Leland Stanford Junior University | Compositions d'oligomères amyloïdes |
WO2023149801A1 (fr) * | 2022-02-03 | 2023-08-10 | Erasmus University Medical Center Rotterdam | Procédé de préparation d'un anticorps spécifique à une conformation |
CN117024554A (zh) * | 2023-05-30 | 2023-11-10 | 中国人民解放军空军军医大学 | 一种Aβ1-42寡聚体存储液的制备方法及其应用 |
Citations (41)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4399216A (en) | 1980-02-25 | 1983-08-16 | The Trustees Of Columbia University | Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials |
US4510245A (en) | 1982-11-18 | 1985-04-09 | Chiron Corporation | Adenovirus promoter system |
US4634665A (en) | 1980-02-25 | 1987-01-06 | The Trustees Of Columbia University In The City Of New York | Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials |
US4816397A (en) | 1983-03-25 | 1989-03-28 | Celltech, Limited | Multichain polypeptides or proteins and processes for their production |
EP0368684A1 (fr) | 1988-11-11 | 1990-05-16 | Medical Research Council | Clonage de séquences d'immunoglobulines de domaines variables. |
US4968615A (en) | 1985-12-18 | 1990-11-06 | Ciba-Geigy Corporation | Deoxyribonucleic acid segment from a virus |
EP0436597A1 (fr) | 1988-09-02 | 1991-07-17 | Protein Eng Corp | Production et selection de proteines de liaison diversifiees de recombinaison. |
WO1991017271A1 (fr) | 1990-05-01 | 1991-11-14 | Affymax Technologies N.V. | Procedes de triage de banques d'adn recombine |
WO1992001047A1 (fr) | 1990-07-10 | 1992-01-23 | Cambridge Antibody Technology Limited | Procede de production de chainon de paires a liaison specifique |
WO1992002551A1 (fr) | 1990-08-02 | 1992-02-20 | B.R. Centre Limited | Procedes de production de proteines presentant une fonction souhaitee |
WO1992009690A2 (fr) | 1990-12-03 | 1992-06-11 | Genentech, Inc. | Methode d'enrichissement pour des variantes de l'hormone de croissance avec des proprietes de liaison modifiees |
WO1992020791A1 (fr) | 1990-07-10 | 1992-11-26 | Cambridge Antibody Technology Limited | Methode de production de chainons de paires de liaison specifique |
US5168062A (en) | 1985-01-30 | 1992-12-01 | University Of Iowa Research Foundation | Transfer vectors and microorganisms containing human cytomegalovirus immediate-early promoter-regulatory DNA sequence |
US5179017A (en) | 1980-02-25 | 1993-01-12 | The Trustees Of Columbia University In The City Of New York | Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials |
US5223409A (en) | 1988-09-02 | 1993-06-29 | Protein Engineering Corp. | Directed evolution of novel binding proteins |
US5545806A (en) | 1990-08-29 | 1996-08-13 | Genpharm International, Inc. | Ransgenic non-human animals for producing heterologous antibodies |
US5569825A (en) | 1990-08-29 | 1996-10-29 | Genpharm International | Transgenic non-human animals capable of producing heterologous antibodies of various isotypes |
WO1996033735A1 (fr) | 1995-04-27 | 1996-10-31 | Abgenix, Inc. | Anticorps humains derives d'une xenosouris immunisee |
WO1996034096A1 (fr) | 1995-04-28 | 1996-10-31 | Abgenix, Inc. | Anticorps humains derives de xeno-souris immunisees |
WO1997008320A1 (fr) | 1995-08-18 | 1997-03-06 | Morphosys Gesellschaft Für Proteinoptimierung Mbh | Banques de proteines/(poly)peptides |
US5625126A (en) | 1990-08-29 | 1997-04-29 | Genpharm International, Inc. | Transgenic non-human animals for producing heterologous antibodies |
US5633425A (en) | 1990-08-29 | 1997-05-27 | Genpharm International, Inc. | Transgenic non-human animals capable of producing heterologous antibodies |
WO1997029131A1 (fr) | 1996-02-09 | 1997-08-14 | Basf Aktiengesellschaft | ANTICORPS HUMAINS SE FIXANT AU FACTEUR NECROSANT DES TUMEURS DE TYPE $g(a) |
US5661016A (en) | 1990-08-29 | 1997-08-26 | Genpharm International Inc. | Transgenic non-human animals capable of producing heterologous antibodies of various isotypes |
WO1998024893A2 (fr) | 1996-12-03 | 1998-06-11 | Abgenix, Inc. | MAMMIFERES TRANSGENIQUES POSSEDANT DES LOCI DE GENES D'IMMUNOGLOBULINE D'ORIGINE HUMAINE, DOTES DE REGIONS VH ET Vλ, ET ANTICORPS PRODUITS A PARTIR DE TELS MAMMIFERES |
US5770429A (en) | 1990-08-29 | 1998-06-23 | Genpharm International, Inc. | Transgenic non-human animals capable of producing heterologous antibodies |
WO1998031700A1 (fr) | 1997-01-21 | 1998-07-23 | The General Hospital Corporation | Selection de proteines a l'aide de fusions arn-proteine |
US5814318A (en) | 1990-08-29 | 1998-09-29 | Genpharm International Inc. | Transgenic non-human animals for producing heterologous antibodies |
WO1998047343A2 (fr) | 1997-04-04 | 1998-10-29 | Biosite Diagnostics, Inc. | Bibliotheques polyvalentes et polyclonales |
WO1998049286A2 (fr) | 1997-05-01 | 1998-11-05 | Board Of Regents, The University Of Texas System | Evolution orientee d'enzymes et d'anticorps |
US5877397A (en) | 1990-08-29 | 1999-03-02 | Genpharm International Inc. | Transgenic non-human animals capable of producing heterologous antibodies of various isotypes |
US5885793A (en) | 1991-12-02 | 1999-03-23 | Medical Research Council | Production of anti-self antibodies from antibody segment repertoires and displayed on phage |
WO1999036569A1 (fr) | 1998-01-20 | 1999-07-22 | The Board Of Trustees Of The University Of Illinois | Proteines pour la presentation de la surface d'une cellule de levure et leurs utilisations |
US5939598A (en) | 1990-01-12 | 1999-08-17 | Abgenix, Inc. | Method of making transgenic mice lacking endogenous heavy chains |
WO1999045962A1 (fr) | 1998-03-13 | 1999-09-16 | Genpharm International, Inc. | Animaux transgeniques capables de fabriquer des anticorps heterologues |
WO1999053049A1 (fr) | 1998-04-15 | 1999-10-21 | Abgenix, Inc. | Production d'anticorps humains par des epitopes et formation de profils d'expression genique |
WO2000056772A1 (fr) | 1999-03-25 | 2000-09-28 | Knoll Gmbh | Anticorps humains se liant a l'interleukine-12 humaine et procedes de production de ces derniers |
WO2001010900A2 (fr) | 1999-08-04 | 2001-02-15 | University Of Southern California | PROTEINE D'AMYLOIDE β (ENSEMBLE GLOBULAIRE ET SES UTILISATIONS) |
US6218506B1 (en) | 1997-02-05 | 2001-04-17 | Northwestern University | Amyloid β protein (globular assembly and uses thereof) |
WO2003016467A2 (fr) | 2001-08-17 | 2003-02-27 | Eli Lilly And Company | Utilisation d'anticorps ayant une forte affinite pour le peptide a$g(b) dans le traitement de pathologies et de maladies liees a a$g(b) |
WO2003016466A2 (fr) | 2001-08-17 | 2003-02-27 | Eli Lilly And Company | Anticorps anti-$g(a)$g(b) |
Family Cites Families (683)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2500076C3 (de) | 1975-01-02 | 1982-11-18 | SCHURA Blutderivate GmbH & Co KG, 4150 Krefeld | Verfahren zur Gewinnung von intravenös-verträglichen Gammaglobulinen |
NO812612L (no) | 1980-08-06 | 1982-02-08 | Ferring Pharma Ltd | Enzym-inhibitorer. |
BR8108820A (pt) | 1980-09-24 | 1982-08-24 | Cetus Corp | Processo e sonda de diagnostico |
DE3381518D1 (de) | 1982-01-22 | 1990-06-07 | Cetus Corp | Verfahren zur charakterisierung von hla und die darin benutzten cdns-testmittel. |
US4582788A (en) | 1982-01-22 | 1986-04-15 | Cetus Corporation | HLA typing method and cDNA probes used therein |
ATE37983T1 (de) | 1982-04-22 | 1988-11-15 | Ici Plc | Mittel mit verzoegerter freigabe. |
US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
US4526039A (en) | 1983-06-23 | 1985-07-02 | The United States Of America As Represented By The Secretary Of Transportation | Removable strain gauge fixture and method for measuring accumulated strain in a material |
US4683194A (en) | 1984-05-29 | 1987-07-28 | Cetus Corporation | Method for detection of polymorphic restriction sites and nucleic acid sequences |
US5807715A (en) | 1984-08-27 | 1998-09-15 | The Board Of Trustees Of The Leland Stanford Junior University | Methods and transformed mammalian lymphocyte cells for producing functional antigen-binding protein including chimeric immunoglobulin |
US5128326A (en) | 1984-12-06 | 1992-07-07 | Biomatrix, Inc. | Drug delivery systems based on hyaluronans derivatives thereof and their salts and methods of producing same |
US4683202A (en) | 1985-03-28 | 1987-07-28 | Cetus Corporation | Process for amplifying nucleic acid sequences |
EP0590689B2 (fr) | 1985-03-30 | 2006-08-16 | KAUFFMAN, Stuart A. | Procédé d'obtention d'ADN, ARN, peptides, polypeptides ou protéines, par une technique de recombinaison d'ADN |
US6492107B1 (en) | 1986-11-20 | 2002-12-10 | Stuart Kauffman | Process for obtaining DNA, RNA, peptides, polypeptides, or protein, by recombinant DNA technique |
US4666829A (en) | 1985-05-15 | 1987-05-19 | University Of California | Polypeptide marker for Alzheimer's disease and its use for diagnosis |
US4980286A (en) | 1985-07-05 | 1990-12-25 | Whitehead Institute For Biomedical Research | In vivo introduction and expression of foreign genetic material in epithelial cells |
US5618920A (en) | 1985-11-01 | 1997-04-08 | Xoma Corporation | Modular assembly of antibody genes, antibodies prepared thereby and use |
DE3600905A1 (de) | 1986-01-15 | 1987-07-16 | Ant Nachrichtentech | Verfahren zum dekodieren von binaersignalen sowie viterbi-dekoder und anwendungen |
CA1284931C (fr) | 1986-03-13 | 1991-06-18 | Henry A. Erlich | Procede de detection de variations specifiques de nucleotides et de polymorphismes genetiques dans les acides nucleiques |
US5225539A (en) | 1986-03-27 | 1993-07-06 | Medical Research Council | Recombinant altered antibodies and methods of making altered antibodies |
GB8607679D0 (en) | 1986-03-27 | 1986-04-30 | Winter G P | Recombinant dna product |
US5107065A (en) | 1986-03-28 | 1992-04-21 | Calgene, Inc. | Anti-sense regulation of gene expression in plant cells |
CA1338457C (fr) | 1986-08-22 | 1996-07-16 | Henry A. Erlich | Enzyme thermostable purifiee |
US5525339A (en) | 1986-08-27 | 1996-06-11 | Dms Pharmaceutical Inc. | Isolated components of dense microspheres derived from mammalian brain tissue and antibodies thereto |
US5231170A (en) | 1986-08-27 | 1993-07-27 | Paul Averback | Antibodies to dense microspheres |
US4946778A (en) | 1987-09-21 | 1990-08-07 | Genex Corporation | Single polypeptide chain binding molecules |
US5811310A (en) | 1986-09-30 | 1998-09-22 | Albert Einstein College Of Medicine Of Yeshiva Univ. | The Alz-50 monoclonal antibody and diagnostic assay for alzheimer's disease |
JPS63240797A (ja) | 1986-10-14 | 1988-10-06 | Shin Etsu Chem Co Ltd | モノクローナル抗体、その製法およびそれを含有する診断薬 |
EP0274826B1 (fr) | 1986-11-17 | 1998-08-12 | Scios Inc. | Protéine recombinante amyloide d'alzheimer |
DE3702789A1 (de) | 1987-01-30 | 1988-08-18 | Bayer Ag | Vorlaeuferprotein des apc-polypeptids, dafuer codierende dna und diagnostische verwendung der dna und des proteins |
DE3883899T3 (de) | 1987-03-18 | 1999-04-22 | Sb2, Inc., Danville, Calif. | Geänderte antikörper. |
JPS63245689A (ja) | 1987-03-31 | 1988-10-12 | Suntory Ltd | ヒトアミロイド関連蛋白モノクロ−ナル抗体 |
US5258498A (en) | 1987-05-21 | 1993-11-02 | Creative Biomolecules, Inc. | Polypeptide linkers for production of biosynthetic proteins |
US4880078A (en) | 1987-06-29 | 1989-11-14 | Honda Giken Kogyo Kabushiki Kaisha | Exhaust muffler |
CA1340802C (fr) | 1987-08-15 | 1999-10-26 | Yasuyuki Takahashi | Proteine precurseur de l'amyloide senile et anticorps specifique pour cette proteine |
US5004697A (en) | 1987-08-17 | 1991-04-02 | Univ. Of Ca | Cationized antibodies for delivery through the blood-brain barrier |
US5231000A (en) | 1987-10-08 | 1993-07-27 | The Mclean Hospital | Antibodies to A4 amyloid peptide |
CA1339014C (fr) | 1987-10-08 | 1997-03-25 | Ronald E. Majocha | Anticorps pour peptide a4-amyloide |
WO1989006689A1 (fr) | 1988-01-13 | 1989-07-27 | The Mclean Hospital Corporation | Constructions genetiques renfermant le gene amyloide cerebral d'alzheimer |
WO1989007657A1 (fr) | 1988-02-10 | 1989-08-24 | The Children's Medical Center Corporation | Precurseurs de proteines amyloides, sondes genetiques, anticorps, et modes d'utilisation |
US5134062A (en) | 1988-03-22 | 1992-07-28 | Cornell Research Foundation, Inc. | Diagnosis of neuronal disorders and screening potential therapeutic agents therefor |
US5015570A (en) | 1988-05-13 | 1991-05-14 | Molecular Therapeutics, Inc. | Molecular diagnosis of Alzheimer Disease |
US6287793B1 (en) | 1988-08-19 | 2001-09-11 | Elan Pharmaceuticals, Inc. | Diagnostic methods for alzheimer's disease |
US20040049014A1 (en) | 1988-12-28 | 2004-03-11 | Protein Design Labs, Inc. | Humanized immunoglobulins |
US5530101A (en) | 1988-12-28 | 1996-06-25 | Protein Design Labs, Inc. | Humanized immunoglobulins |
US5231020A (en) | 1989-03-30 | 1993-07-27 | Dna Plant Technology Corporation | Genetic engineering of novel plant phenotypes |
US5262332A (en) | 1989-04-05 | 1993-11-16 | Brigham And Women's Hospital | Diagnostic method for Alzheimer's disease: examination of non-neural tissue |
AU5525090A (en) | 1989-04-14 | 1990-11-16 | Research Foundation For Mental Hygiene, Inc. | Monoclonal antibody to amyloid peptide |
CA2057923A1 (fr) | 1989-05-16 | 1990-11-17 | William D. Huse | Co-expression de recepteurs heteromeriques |
CA2016842A1 (fr) | 1989-05-16 | 1990-11-16 | Richard A. Lerner | Methode pour puiser dans le repertoire immunologique |
CA2016841C (fr) | 1989-05-16 | 1999-09-21 | William D. Huse | Methode de production de polymeres ayant une activite choisie |
US5234814A (en) | 1989-06-01 | 1993-08-10 | Du Pont Merck Pharmaceutical Company | Diagnostic assay for alzheimer's disease |
EP0415801A1 (fr) | 1989-07-05 | 1991-03-06 | N.V. Innogenetics S.A. | Anticorps monoclonaux contre cellules microglia activées |
EP0411974A1 (fr) | 1989-07-05 | 1991-02-06 | N.V. Innogenetics S.A. | Anticorps monoclonaux contre une antigène d'enchevêtrements neurofibrillaires |
AU6430190A (en) | 1989-10-10 | 1991-05-16 | Pitman-Moore, Inc. | Sustained release composition for macromolecular proteins |
WO1991006287A1 (fr) | 1989-11-06 | 1991-05-16 | Enzytech, Inc. | Microspheres de proteines et leurs procedes d'utilisation |
GB8928874D0 (en) | 1989-12-21 | 1990-02-28 | Celltech Ltd | Humanised antibodies |
US5780225A (en) | 1990-01-12 | 1998-07-14 | Stratagene | Method for generating libaries of antibody genes comprising amplification of diverse antibody DNAs and methods for using these libraries for the production of diverse antigen combining molecules |
AU7247191A (en) | 1990-01-11 | 1991-08-05 | Molecular Affinities Corporation | Production of antibodies using gene libraries |
US6075181A (en) | 1990-01-12 | 2000-06-13 | Abgenix, Inc. | Human antibodies derived from immunized xenomice |
AU7121191A (en) | 1990-02-26 | 1991-10-10 | Albert Einstein College Of Medicine Of Yeshiva University | Diagnostic assay for alzheimer's disease |
US5753624A (en) | 1990-04-27 | 1998-05-19 | Milkhaus Laboratory, Inc. | Materials and methods for treatment of plaquing disease |
DE4022247A1 (de) | 1990-07-12 | 1992-01-16 | Hoechst Ag | Verfahren zur extraktiven abtrennung von 2-alkylthio-5-phenylpyrimidinen aus ihren reaktionsgemischen |
US5698426A (en) | 1990-09-28 | 1997-12-16 | Ixsys, Incorporated | Surface expression libraries of heteromeric receptors |
AU1545692A (en) | 1991-03-01 | 1992-10-06 | Protein Engineering Corporation | Process for the development of binding mini-proteins |
CA2108147C (fr) | 1991-04-10 | 2009-01-06 | Angray Kang | Banques de recepteurs heterodimeriques construites a l'aide de phagemides |
ATE221379T1 (de) | 1991-05-01 | 2002-08-15 | Jackson H M Found Military Med | Verfahren zur behandlung infektiöser respiratorischer erkrankungen |
JPH04342883A (ja) | 1991-05-17 | 1992-11-30 | Sanden Corp | 容量可変型斜板式圧縮機 |
EP0519596B1 (fr) | 1991-05-17 | 2005-02-23 | Merck & Co. Inc. | Procédé pour réduire l'immunogénicité des domaines variables d'anticorps |
EP0590067A1 (fr) | 1991-06-14 | 1994-04-06 | Xoma Corporation | Fragments d'anticorps produits par des microbes et leurs conjugues |
DE4122599C2 (de) | 1991-07-08 | 1993-11-11 | Deutsches Krebsforsch | Phagemid zum Screenen von Antikörpern |
ES2136092T3 (es) | 1991-09-23 | 1999-11-16 | Medical Res Council | Procedimientos para la produccion de anticuerpos humanizados. |
DE69220503T2 (de) | 1991-10-25 | 1998-02-05 | Innogenetics Nv | Monoklonale Antikörper gegen das mikrotubulusassoziierte Protein Tau. |
DE69227380T3 (de) | 1991-11-12 | 2007-01-11 | Prana Biotechnology Ltd., South Melbourne | Verfahren zur bestimmung und behandlung von alzheimer-krankheit |
US20020009443A1 (en) | 1991-12-02 | 2002-01-24 | Vanitha Ramakrishman | Inhibitory immunoglobulin polypeptides to human pdgf beta receptor |
WO1993011231A1 (fr) | 1991-12-06 | 1993-06-10 | MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. | Outils de diagnostic et de traitement de la maladie d'alzheimer |
US7408027B1 (en) | 1991-12-06 | 2008-08-05 | Max-Planck-Gesellschaft Zur Forderung Der Wissenchaften | Tools for the diagnosis and treatment of Alzheimer's disease |
EP0571613B1 (fr) | 1991-12-13 | 2003-09-17 | Xoma Corporation | Materiels et methodes pour preparer des domaines variables d'anticorps modifies et leurs utilisations therapeutiques |
US20010029293A1 (en) | 1992-01-27 | 2001-10-11 | Icos Corporation | Icam-related protein |
US5538845A (en) | 1992-02-05 | 1996-07-23 | Athena Neurosciences, Inc. | Beta-amyloid peptide production inhibitors and methods for their identification |
US5714350A (en) | 1992-03-09 | 1998-02-03 | Protein Design Labs, Inc. | Increasing antibody affinity by altering glycosylation in the immunoglobulin variable region |
US5912015A (en) | 1992-03-12 | 1999-06-15 | Alkermes Controlled Therapeutics, Inc. | Modulated release from biocompatible polymers |
US5733743A (en) | 1992-03-24 | 1998-03-31 | Cambridge Antibody Technology Limited | Methods for producing members of specific binding pairs |
US5912120A (en) | 1992-04-09 | 1999-06-15 | The United States Of America As Represented By The Department Of Health And Human Services, | Cloning, expression and diagnosis of human cytochrome P450 2C19: the principal determinant of s-mephenytoin metabolism |
US5441870A (en) | 1992-04-15 | 1995-08-15 | Athena Neurosciences, Inc. | Methods for monitoring cellular processing of β-amyloid precursor protein |
US5604102A (en) | 1992-04-15 | 1997-02-18 | Athena Neurosciences, Inc. | Methods of screening for β-amyloid peptide production inhibitors |
US5455169A (en) | 1992-06-04 | 1995-10-03 | Alzheimer's Institute Of America, Inc. | Nucleic acids for diagnosing and modeling Alzheimer's disease |
US6610493B1 (en) | 1993-06-17 | 2003-08-26 | Brigham And Women's Hospital | Screening compounds for the ability to alter the production of amyloid-β peptide |
US5837672A (en) | 1992-07-10 | 1998-11-17 | Athena Neurosciences, Inc. | Methods and compositions for the detection of soluble β-amyloid peptide |
US5766846A (en) | 1992-07-10 | 1998-06-16 | Athena Neurosciences | Methods of screening for compounds which inhibit soluble β-amyloid peptide production |
WO1994002602A1 (fr) | 1992-07-24 | 1994-02-03 | Cell Genesys, Inc. | Production d'anticorps xenogeniques |
US5639641A (en) | 1992-09-09 | 1997-06-17 | Immunogen Inc. | Resurfacing of rodent antibodies |
TW258789B (fr) | 1992-09-28 | 1995-10-01 | Rohm & Haas | |
US5605811A (en) | 1992-10-26 | 1997-02-25 | Athena Neurosciences, Inc. | Methods and compositions for monitoring cellular processing of beta-amyloid precursor protein |
US5891623A (en) | 1992-11-09 | 1999-04-06 | Consorzio Per Le Biotecnologie | Diagnosis and treatment of AIDS onset |
ZA938243B (en) | 1992-11-12 | 1995-05-04 | Hybritech Inc | Altered affinity polypeptides of metal chelate binding antibodies |
US6010913A (en) | 1992-12-14 | 2000-01-04 | N.V. Innogenetics S.A. | Isolated human tau peptide |
US5955317A (en) | 1993-01-25 | 1999-09-21 | Takeda Chemical Industries, Ltd. | Antibodies to β-amyloids or their derivatives and use thereof |
EP1308461A3 (fr) | 1993-01-25 | 2004-02-11 | Takeda Chemical Industries, Ltd. | Anticorps contre des bèta-amyloides ou leurs dérivés, et leurs utilisations |
US5934272A (en) | 1993-01-29 | 1999-08-10 | Aradigm Corporation | Device and method of creating aerosolized mist of respiratory drug |
CA2115900A1 (fr) | 1993-02-22 | 1994-08-23 | Gerald W. Becker | Cribles pharmaceutiques et anticorps |
US5840294A (en) | 1993-03-29 | 1998-11-24 | Queen's University At Kingston | Method for treating amyloidosis |
AU698962B2 (en) | 1993-09-14 | 1998-11-12 | Epimmune, Inc. | Alteration of immune response using pan DR-binding peptides |
ATE213507T1 (de) | 1993-10-20 | 2002-03-15 | Univ Duke | Methode zur bindung von material an das beta- amyloid-peptid |
US5565352A (en) | 1993-11-24 | 1996-10-15 | Arch Development Corporation | Deubiquitinating enzyme: compositions and methods |
EP0733070A1 (fr) | 1993-12-08 | 1996-09-25 | Genzyme Corporation | Procede de generation d'anticorps specifiques |
AU1397495A (en) | 1993-12-13 | 1995-07-03 | Uab Research Foundation, The | Diagnostic tests and reagents for detecting risk of alzheimer's disease and stroke |
US6432404B1 (en) | 1993-12-23 | 2002-08-13 | Icos Corporation | Methods of inhibiting locomotor damage following spinal cord injury with α D-specific antibodies |
US6620915B2 (en) | 1993-12-23 | 2003-09-16 | Icos Corporation | Monoclonal antibodies specific for integrin α-d subunit |
US6251395B1 (en) | 1993-12-23 | 2001-06-26 | W. Michael Gallatin | Methods of inhibiting inflammation at the site of a central nervous system injury with alphaD-specific antibodies |
US5877399A (en) | 1994-01-27 | 1999-03-02 | Johns Hopkins University | Transgenic mice expressing APP-Swedish mutation develop progressive neurologic disease |
ES2247204T3 (es) | 1994-01-31 | 2006-03-01 | Trustees Of Boston University | Bancos de anticuerpos policlonales. |
JPH07238096A (ja) | 1994-02-25 | 1995-09-12 | S R L:Kk | 抗ポリユビキチン・モノクローナル抗体およびポリユビキチンの測定方法 |
US7473423B2 (en) | 1994-04-29 | 2009-01-06 | Mayo Foundation For Medical Education And Research | Human IgM antibodies, and diagnostic and therapeutic uses thereof particularly in the central nervous system |
US5516637A (en) | 1994-06-10 | 1996-05-14 | Dade International Inc. | Method involving display of protein binding pairs on the surface of bacterial pili and bacteriophage |
US6018021A (en) | 1994-10-19 | 2000-01-25 | The Research Foundation Of State University Of New York | Human transaldolase: an autoantigen with a function in metabolism |
US6114133A (en) | 1994-11-14 | 2000-09-05 | Elan Pharmaceuticals, Inc. | Methods for aiding in the diagnosis of Alzheimer's disease by measuring amyloid-β peptide (x-≧41) |
EP0805678B1 (fr) | 1995-01-05 | 2003-10-29 | THE BOARD OF REGENTS acting for and on behalf of THE UNIVERSITY OF MICHIGAN | Nanoparticules a modification de surface et leurs procedes de fabrication et d'utilisation |
US5786180A (en) | 1995-02-14 | 1998-07-28 | Bayer Corporation | Monoclonal antibody 369.2B specific for β A4 peptide |
JP3663228B2 (ja) | 1995-03-14 | 2005-06-22 | 株式会社医学生物学研究所 | ニューロプシンに対する抗体 |
US6091001A (en) | 1995-03-29 | 2000-07-18 | Abgenix, Inc. | Production of antibodies using Cre-mediated site-specific recombination |
US6130364A (en) | 1995-03-29 | 2000-10-10 | Abgenix, Inc. | Production of antibodies using Cre-mediated site-specific recombination |
US5705330A (en) | 1995-04-14 | 1998-01-06 | Abbott Laboratories | Chemiluminescent immunoassay for antibody detection |
US6019968A (en) | 1995-04-14 | 2000-02-01 | Inhale Therapeutic Systems, Inc. | Dispersible antibody compositions and methods for their preparation and use |
JP3392627B2 (ja) | 1995-04-17 | 2003-03-31 | 三洋電機株式会社 | 2次元映像を3次元映像に変換する方法 |
WO1996033266A1 (fr) | 1995-04-21 | 1996-10-24 | Cell Genesys, Inc. | Creation d'importantes deletions d'adn genomique |
US5712158A (en) | 1995-06-06 | 1998-01-27 | Warner-Lambert Company | Cell line for the rapid expression of functional calcium channels |
US6717031B2 (en) | 1995-06-07 | 2004-04-06 | Kate Dora Games | Method for selecting a transgenic mouse model of alzheimer's disease |
WO1996040731A1 (fr) | 1995-06-07 | 1996-12-19 | Mount Sinai School Of Medicine Of The City University Of New York | Proteines modifiees conjuguees a du polyethylene-glycol (peg) |
JP3081512B2 (ja) | 1995-06-21 | 2000-08-28 | 三洋電機株式会社 | 立体映像装置 |
JP3767755B2 (ja) | 1995-06-23 | 2006-04-19 | エーザイ株式会社 | 抗jcウイルス抗体 |
US6127977A (en) | 1996-11-08 | 2000-10-03 | Cohen; Nathan | Microstrip patch antenna with fractal structure |
US5916597A (en) | 1995-08-31 | 1999-06-29 | Alkermes Controlled Therapeutics, Inc. | Composition and method using solid-phase particles for sustained in vivo release of a biologically active agent |
DE69632056T2 (de) | 1995-09-14 | 2004-12-30 | The Regents Of The University Of California, Oakland | Für natives prp-sc spezifische antikörper |
FR2740454B1 (fr) | 1995-10-26 | 1997-11-21 | Rhone Poulenc Rorer Sa | Peptides capables d'inhiber l'endocytose de l'app et sequences nucleotidiques correspondantes |
AUPN649395A0 (en) | 1995-11-10 | 1995-12-07 | Ramsay Health Care Pty Ltd | A method for diagnosing alzheimer's disease |
FR2741881B1 (fr) | 1995-12-01 | 1999-07-30 | Centre Nat Rech Scient | Nouveaux derives de purine possedant notamment des prorietes anti-proliferatives et leurs applications biologiques |
WO1997021807A1 (fr) | 1995-12-12 | 1997-06-19 | Kyowa Hakko Kogyo Co., Ltd. | Nouveaux adn, nouveaux polypeptides et nouveaux anticorps |
JPH09178743A (ja) | 1995-12-27 | 1997-07-11 | Oriental Yeast Co Ltd | 可溶性appの定量法 |
ATE219247T1 (de) | 1996-01-19 | 2002-06-15 | Res Corp Technologies Inc | Methoden zur feststellung von alzheimerscher krankheit |
JP2978435B2 (ja) | 1996-01-24 | 1999-11-15 | チッソ株式会社 | アクリロキシプロピルシランの製造方法 |
EP0948536B1 (fr) | 1996-01-30 | 2007-06-13 | The Scripps Research Institute | Recepteur associe a la proteine g presentant un domaine extracellulaire agrandi |
AU2063197A (en) | 1996-03-04 | 1997-09-22 | Massachusetts Institute Of Technology | Materials and methods for enhancing cellular internalization |
US5714352A (en) | 1996-03-20 | 1998-02-03 | Xenotech Incorporated | Directed switch-mediated DNA recombination |
US5882644A (en) | 1996-03-22 | 1999-03-16 | Protein Design Labs, Inc. | Monoclonal antibodies specific for the platelet derived growth factor β receptor and methods of use thereof |
US5874064A (en) | 1996-05-24 | 1999-02-23 | Massachusetts Institute Of Technology | Aerodynamically light particles for pulmonary drug delivery |
US5855913A (en) | 1997-01-16 | 1999-01-05 | Massachusetts Instite Of Technology | Particles incorporating surfactants for pulmonary drug delivery |
US5985309A (en) | 1996-05-24 | 1999-11-16 | Massachusetts Institute Of Technology | Preparation of particles for inhalation |
US6699658B1 (en) | 1996-05-31 | 2004-03-02 | Board Of Trustees Of The University Of Illinois | Yeast cell surface display of proteins and uses thereof |
WO1997046678A1 (fr) | 1996-06-06 | 1997-12-11 | Bayer Corporation | Acides nucleiques et polypeptides apparentes a la preseniline |
JPH109900A (ja) | 1996-06-21 | 1998-01-16 | Kanto Auto Works Ltd | メ−タ指針 |
WO1999009150A1 (fr) | 1996-08-15 | 1999-02-25 | Bayer Corporation | Methode permettant d'introduire des modifications dans un gene |
CA2183901A1 (fr) | 1996-08-22 | 1998-02-23 | Johanna E. Bergmann | Cibles pour le traitement et le diagnostic de la maladie d'alzheimer et du syndrome de down chez les humains |
US7521531B2 (en) | 1996-08-28 | 2009-04-21 | Immunomedics, Inc. | Methods for the purification of stable radioiodine conjugates |
JPH1075781A (ja) | 1996-08-30 | 1998-03-24 | Sumitomo Electric Ind Ltd | ヒトプロテアソームサブユニットp58蛋白質及びそれに特異的な抗体 |
EP0834561A1 (fr) | 1996-09-27 | 1998-04-08 | Rijksuniversiteit te Leiden | Gène associé avec la migraine dans l'humain |
US5916771A (en) | 1996-10-11 | 1999-06-29 | Abgenix, Inc. | Production of a multimeric protein by cell fusion method |
WO1998022120A1 (fr) | 1996-11-19 | 1998-05-28 | The Wistar Institute Of Anatomy & Biology | Reactifs pour traiter et diagnostiquer la maladie d'alzheimer |
US5919687A (en) | 1996-12-24 | 1999-07-06 | John Hopkins University | Recombinant N-SMases and nucleic acids encoding same |
PT954282E (pt) | 1997-01-16 | 2005-06-30 | Massachusetts Inst Technology | Preparacao de particulas para inalacao |
JPH10210982A (ja) | 1997-01-31 | 1998-08-11 | Fuji Yakuhin Kogyo Kk | 新規なタンパク質 |
US20030068316A1 (en) * | 1997-02-05 | 2003-04-10 | Klein William L. | Anti-ADDL antibodies and uses thereof |
US6413940B1 (en) | 1997-02-07 | 2002-07-02 | Nymox Corporation | Pharmaceutically active agents that impede the formation of amyloid by impeding the genesis of DMS |
US7226730B1 (en) | 1997-02-26 | 2007-06-05 | The General Hospital Corporation | Transgenic animals and cell lines for screening drugs effective for the treatment or prevention of Alzheimer's Disease |
US7045531B1 (en) | 1997-03-11 | 2006-05-16 | The General Hospital Corporation | Composition comprising a metal chelator and a method of treating amyloidosis by administering the metal chelator |
JP4740426B2 (ja) | 1997-03-17 | 2011-08-03 | ビーティージー・インターナショナル・リミテッド | 治療用組成物 |
US20020086847A1 (en) | 1997-04-09 | 2002-07-04 | Mindset Biopharmaceuticals (Usa) | Recombinant antibodies specific for beta-amyloid ends, DNA encoding and methods of use thereof |
US8173127B2 (en) | 1997-04-09 | 2012-05-08 | Intellect Neurosciences, Inc. | Specific antibodies to amyloid beta peptide, pharmaceutical compositions and methods of use thereof |
US6235883B1 (en) | 1997-05-05 | 2001-05-22 | Abgenix, Inc. | Human monoclonal antibodies to epidermal growth factor receptor |
EP1860187B1 (fr) | 1997-05-15 | 2011-07-13 | Genentech, Inc. | Récepteur apo-2 |
KR100567277B1 (ko) | 1997-07-21 | 2006-04-05 | 마토씨안-로저스, 알피 | 항-항-t 세포 수용체 브이베타 항체 또는 이 항체에 의해 인식되는 펩티드 및 내분비선 분비 조절 단백질 i(esrp1)을 사용하는 질병의 진단 및 치료 방법 |
IT1293511B1 (it) | 1997-07-30 | 1999-03-01 | Gentili Ist Spa | Anticorpi monoclonali catalitici ad attivita' proteasica per la lisi selettiva della componente proteica di placche e aggregati correlati |
ES2281135T3 (es) | 1997-08-14 | 2007-09-16 | Institut Pasteur | Proteinas hibridas de un toxoide tetanico que migran de forma retrograda y transinaptica al snc. |
US7923216B2 (en) | 1997-08-14 | 2011-04-12 | Institut Pasteur | In vivo modulation of neuronal transport |
EP1007092B1 (fr) | 1997-08-26 | 2006-08-09 | Amgen Fremont Inc. | Procede d'inhibition d'activation de complement par la voie alterne |
US6666935B1 (en) | 1997-09-09 | 2003-12-23 | The Regents Of The University Of California | Sol-gel manufactured energetic materials |
FR2768346B1 (fr) | 1997-09-15 | 2002-04-19 | Fond Jean Dausset Ceph | Compose assurant l'inhibition de la preseniline 1 pour la preparation d'un medicament et agent de diagnostic |
US20040185039A1 (en) | 2002-08-30 | 2004-09-23 | Heinz Kohler | Therapeutic applications of noncovalent dimerizing antibodies |
US5989463A (en) | 1997-09-24 | 1999-11-23 | Alkermes Controlled Therapeutics, Inc. | Methods for fabricating polymer-based controlled release devices |
SE512663C2 (sv) | 1997-10-23 | 2000-04-17 | Biogram Ab | Inkapslingsförfarande för aktiv substans i en bionedbrytbar polymer |
WO1999022024A1 (fr) | 1997-10-24 | 1999-05-06 | Cornell Research Foundation, Inc. | Detection de maladies neurodegeneratives |
US6710226B1 (en) | 1997-12-02 | 2004-03-23 | Neuralab Limited | Transgenic mouse assay to determine the effect of Aβ antibodies and Aβ Fragments on alzheimer's disease characteristics |
TWI239847B (en) | 1997-12-02 | 2005-09-21 | Elan Pharm Inc | N-terminal fragment of Abeta peptide and an adjuvant for preventing and treating amyloidogenic disease |
US6913745B1 (en) | 1997-12-02 | 2005-07-05 | Neuralab Limited | Passive immunization of Alzheimer's disease |
US6761888B1 (en) | 2000-05-26 | 2004-07-13 | Neuralab Limited | Passive immunization treatment of Alzheimer's disease |
US7964192B1 (en) | 1997-12-02 | 2011-06-21 | Janssen Alzheimer Immunotherapy | Prevention and treatment of amyloidgenic disease |
US6750324B1 (en) | 1997-12-02 | 2004-06-15 | Neuralab Limited | Humanized and chimeric N-terminal amyloid beta-antibodies |
US6787523B1 (en) | 1997-12-02 | 2004-09-07 | Neuralab Limited | Prevention and treatment of amyloidogenic disease |
US7179892B2 (en) | 2000-12-06 | 2007-02-20 | Neuralab Limited | Humanized antibodies that recognize beta amyloid peptide |
US6743427B1 (en) | 1997-12-02 | 2004-06-01 | Neuralab Limited | Prevention and treatment of amyloidogenic disease |
WO1999027949A1 (fr) | 1997-12-03 | 1999-06-10 | Brigham And Women's Hospital | PROCEDES DE SUPPRESSION DES MODIFICATIONS LIEES AUX β-AMYLOIDES DANS LA MALADIE D'ALZHEIMER |
EP1038958A4 (fr) | 1997-12-15 | 2002-10-09 | Kyowa Hakko Kogyo Kk | PROTEINE Nap1 HUMAINE |
US6730778B2 (en) | 1997-12-19 | 2004-05-04 | Pharmacia And Upjohn Company | Human sel-10 polypeptides and polynucleotides that encode them |
US6436989B1 (en) | 1997-12-24 | 2002-08-20 | Vertex Pharmaceuticals, Incorporated | Prodrugs of aspartyl protease inhibitors |
US7189703B2 (en) | 1998-01-09 | 2007-03-13 | Intracell, Llc | Treatment and diagnosis of alzheimer's disease |
MX2008014823A (es) | 1998-02-11 | 2009-03-06 | Neurochem Int Ltd | Metodo para modular la activacion de macrofagos. |
JP2002505097A (ja) | 1998-03-03 | 2002-02-19 | アブジェニックス インク. | 治療薬としてのcd147結合分子 |
US6323218B1 (en) | 1998-03-11 | 2001-11-27 | The General Hospital Corporation | Agents for use in the treatment of Alzheimer's disease |
US20050112543A1 (en) | 1998-03-11 | 2005-05-26 | The General Hospital Corporation | Method of screening for drugs useful in treating Alzheimer's disease |
US20050059802A1 (en) | 1998-04-07 | 2005-03-17 | Neuralab Ltd | Prevention and treatment of amyloidogenic disease |
US20050059591A1 (en) | 1998-04-07 | 2005-03-17 | Neuralab Limited | Prevention and treatment of amyloidogenic disease |
NO314086B1 (no) | 1998-05-08 | 2003-01-27 | Gemvax As | Peptider og farmasöytiske sammensetninger inneholdende disse, nukleinsyresekvenser som koder for slike peptider, plasmider og virusvektoreromfattende slike DNA-sekvenser samt anvendelse av disse for fremstilling avfarmasöytiske preparater til |
WO1999058157A1 (fr) | 1998-05-08 | 1999-11-18 | Cramer Donald V | Procede d'inhibition de rejet induit par anticorps de tissus heterologues |
AU3726299A (en) | 1998-05-15 | 1999-12-06 | Neurochem, Inc. | Use of amyloid inhibitors for modulating neuronal cell death |
US20030147882A1 (en) | 1998-05-21 | 2003-08-07 | Alan Solomon | Methods for amyloid removal using anti-amyloid antibodies |
DE69913520T2 (de) | 1998-06-01 | 2004-11-25 | Ortho-Mcneil Pharmaceutical, Inc. | Tetrahydronaphtalene verbindungen und deren verwendung zur behandlung von neurodegenerativen krankheiten |
JP2000050885A (ja) | 1998-06-02 | 2000-02-22 | Fuji Chemical Industries Ltd | カテプシンに対する抗体およびそれらの利用 |
DE69907456T2 (de) | 1998-06-24 | 2004-03-25 | Advanced Inhalation Research, Inc., Cambridge | Grosse poröse partikel ausgestossen von einem inhalator |
DK1092767T3 (da) | 1998-07-02 | 2006-11-27 | Fuso Pharmaceutical Ind | Serinproteasespecifikke monoklonale antistoffer og anvendelse deraf |
EP1105427A2 (fr) | 1998-08-17 | 2001-06-13 | Abgenix, Inc. | Production de molecules modifiees avec demi-vie serique prolongee |
US20030109672A1 (en) | 1998-09-01 | 2003-06-12 | Genentech, Inc. | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
JP4403443B2 (ja) | 1998-09-17 | 2010-01-27 | 大塚製薬株式会社 | Ly6h遺伝子 |
US7083950B2 (en) | 1998-09-25 | 2006-08-01 | Regeneron Pharmaceuticals, Inc. | High affinity fusion proteins and therapeutic and diagnostic methods for use |
AU5999199A (en) | 1998-09-29 | 2000-04-17 | Kyowa Hakko Kogyo Co. Ltd. | Novel antibodies, drugs containing these antibodies and methods for screening compounds by using these antibodies |
US6660843B1 (en) | 1998-10-23 | 2003-12-09 | Amgen Inc. | Modified peptides as therapeutic agents |
WO2000032805A1 (fr) | 1998-12-02 | 2000-06-08 | The Trustees Of The University Of Pennsylvania | Procedes et compositions permettant de determiner la peroxydation des lipides dans des syndromes et maladies lies au stress du aux oxydants |
EP1731913A3 (fr) | 1998-12-02 | 2007-01-17 | The Trustees Of The University Of Pennsylvania | Procédés et compositions permettant de déterminer la peroxydation des lipides dans des syndromes et maladies liés au stress du aux oxydants |
ATE364617T1 (de) | 1998-12-14 | 2007-07-15 | Univ Miami | Fragmente des wachstumsfaktors für bindegewebe (ctgf) und verfahren und anwendungen davon |
RS51309B (sr) | 1998-12-23 | 2010-12-31 | Pfizer Inc. | Humana monoklonalna antitela za ctla-4 |
DE19902550A1 (de) | 1999-01-22 | 2000-07-27 | Memorec Medical Molecular Rese | Aspartatprotease |
US20030185826A1 (en) | 1999-02-24 | 2003-10-02 | Tobinick Edward L. | Cytokine antagonists for the treatment of localized disorders |
FR2791263B1 (fr) | 1999-03-26 | 2001-04-27 | Halina Zofia Malina | Preparations des medicaments bases sur une reponse immunitaire contre l'accumulation de proteines modifiees par l'acide xanthurenique |
ES2571230T3 (es) | 1999-04-09 | 2016-05-24 | Kyowa Hakko Kirin Co Ltd | Procedimiento para controlar la actividad de una molécula inmunofuncional |
US7527787B2 (en) | 2005-10-19 | 2009-05-05 | Ibc Pharmaceuticals, Inc. | Multivalent immunoglobulin-based bioactive assemblies |
US6787637B1 (en) | 1999-05-28 | 2004-09-07 | Neuralab Limited | N-Terminal amyloid-β antibodies |
PE20010212A1 (es) | 1999-06-01 | 2001-02-22 | Neuralab Ltd | Composiciones del peptido a-beta y procesos para producir las mismas |
UA81216C2 (en) | 1999-06-01 | 2007-12-25 | Prevention and treatment of amyloid disease | |
US20030199103A1 (en) | 1999-06-03 | 2003-10-23 | Curagen Corporation | Novel amino acid sequences for human epidermal growth factor-like polypeptides |
JP2000354487A (ja) | 1999-06-15 | 2000-12-26 | Takashi Muramatsu | ミッドカイン受容体 |
ATE405636T1 (de) | 1999-06-16 | 2008-09-15 | Boston Biomedical Res Inst | Immunologische kontrolle des beta-amyloid gehaltes in vivo |
US20020002270A1 (en) | 1999-06-16 | 2002-01-03 | Raymond P. Zinkowski | Purified antigen for alzheimer's disease, and methods of obtaining and using same |
US7605238B2 (en) | 1999-08-24 | 2009-10-20 | Medarex, Inc. | Human CTLA-4 antibodies and their uses |
CA2381770C (fr) | 1999-08-24 | 2007-08-07 | Medarex, Inc. | Anticorps contre l'antigene ctla-4 humain et utilisation |
EP1210464B1 (fr) | 1999-09-01 | 2004-11-24 | EVOTEC Neurosciences GmbH | Procede de diagnostic ou de pronostic de la degenerescence maculaire liee a l'age |
US20040013647A1 (en) | 1999-09-03 | 2004-01-22 | Ramot At Tel-Aviv University Ltd. | Methods and compositions for treating a plaque-forming disease |
IL142948A0 (en) | 1999-09-03 | 2002-04-21 | Univ Ramot | Agents and compositions and methods utilizing same useful in diagnosing and/or treating or preventing plaque forming diseases |
US6294171B2 (en) | 1999-09-14 | 2001-09-25 | Milkhaus Laboratory, Inc. | Methods for treating disease states comprising administration of low levels of antibodies |
JP2001122900A (ja) | 1999-10-21 | 2001-05-08 | Yasukazu Tanuma | 抗−DNaseγ抗体並びにその製造及び使用 |
WO2001032712A2 (fr) | 1999-11-03 | 2001-05-10 | Maxygen, Inc. | Generation de diversite d'anticorps |
US20020094335A1 (en) | 1999-11-29 | 2002-07-18 | Robert Chalifour | Vaccine for the prevention and treatment of alzheimer's and amyloid related diseases |
CN1433321A (zh) | 1999-11-29 | 2003-07-30 | 尼奥切姆公司 | 预防和治疗Alzheimer症和其他与淀粉样蛋白有关的疾病的疫苗 |
US20070135337A2 (en) | 1999-11-29 | 2007-06-14 | Neurochem (International) Limited | Vaccine for the Prevention and Treatment of Alzheimer's and Amyloid Related Diseases |
CA2393763A1 (fr) | 1999-12-08 | 2001-06-14 | Mindset Biopharmaceuticals (Usa), Inc. | Peptides chimeriques comme immunogenes, anticorps contre ces immunogenes et techniques d'immunisation utilisant ces peptides chimeriques ou ces anticorps |
EP1752472A3 (fr) | 1999-12-08 | 2007-04-25 | Intellect Neurosciences, Inc. | Peptides amyloides beta chimériques |
JP2001231578A (ja) | 1999-12-09 | 2001-08-28 | Kyowa Hakko Kogyo Co Ltd | Il−1ファミリーに属する蛋白質 |
EP1251837A2 (fr) | 1999-12-23 | 2002-10-30 | Neurochem, Inc. | Composes et methodes permettant la modulation de l'angiopathie cerebrale amyloide |
US20030077757A1 (en) | 2000-01-11 | 2003-04-24 | Andrews William H. | Method of treating aging-related disorders |
US6785434B2 (en) | 2000-01-17 | 2004-08-31 | Avanex Corporation | Attenuator integrated with modulator and transmitting module for WDM systems using the same |
WO2001053457A2 (fr) * | 2000-01-21 | 2001-07-26 | University Of Connecticut Health Center | Vaccins contre certains troubles neurodegeneratifs |
US6806254B2 (en) | 2000-02-03 | 2004-10-19 | Nuvelo, Inc. | Methods and materials relating to alpha-2-macroglobulin-like polypeptides and polynucleotides |
US20020182660A1 (en) | 2000-02-18 | 2002-12-05 | Fong Kei-Lai L. | N- and C-terminus specific immunoassays for full length beta-amyloid peptide-Abeta(1-40), Abeta(1-39), Abeta(1-40), Abeta(1-42) , and Abeta(1-43) |
MXPA02007796A (es) | 2000-02-21 | 2003-12-08 | Pharmexa As | Metodo novedoso para la disminucion de cuerpos amiloides. |
EP1259251B1 (fr) | 2000-02-21 | 2005-10-19 | Pharmexa A/S | Nouvelle methode de regulation negative d'amyloide |
AU4178601A (en) | 2000-02-24 | 2001-09-03 | Univ Washington | Humanized antibodies that sequester abeta peptide |
EP1130032A1 (fr) | 2000-02-28 | 2001-09-05 | Gesellschaft für biotechnologische Forschung mbH (GBF) | Anticorps monochaines reconnaissant le récepteur humain de type 2 du facteur de croissance vasculaire endothéliale (VEGFR-2/KDR) |
GB0006398D0 (en) | 2000-03-16 | 2000-05-03 | Novartis Ag | Organic compounds |
WO2001071351A1 (fr) | 2000-03-22 | 2001-09-27 | The General Hospital Corporation | Procede destine au traitement des maladies neurodegeneratives |
WO2001075165A2 (fr) | 2000-03-30 | 2001-10-11 | Elan Pharmaceuticals, Inc. | Marqueurs et methodes de criblage pour maladies neurodegeneratives |
AU2001249835A1 (en) | 2000-04-03 | 2001-10-15 | Oxford Glycosciences (Uk) Ltd. | Diagnosis and treatment of alzheimer's disease |
US7371365B2 (en) | 2000-04-04 | 2008-05-13 | Mayo Foundation For Medical Education And Research | Methods for detecting parenchymal plaques in vivo |
AUPQ712000A0 (en) | 2000-04-27 | 2000-05-18 | Medvet Science Pty. Ltd. | Antigenic peptide fragments of VapA protein, and uses thereof |
US20080009467A1 (en) | 2000-05-01 | 2008-01-10 | Accera, Inc. | Combinations of medium chain triglycerides and therapeutic agents for the treatment and prevention of alzheimers disease and other diseases resulting from reduced neuronal metabolism |
WO2001083525A2 (fr) | 2000-05-03 | 2001-11-08 | Amgen Inc. | Peptides modifies utilises comme agents therapeutiques |
AU7487301A (en) | 2000-05-22 | 2001-12-03 | Univ New York | Synthetic immunogenic but non-amyloidogenic peptides homologous to amyloid beta for induction of an immune response to amyloid beta and amyloid deposits |
JP2004500873A (ja) | 2000-06-22 | 2004-01-15 | ジェネンテック・インコーポレーテッド | アゴニスト抗−trk−cモノクローナル抗体 |
JP4252195B2 (ja) | 2000-06-27 | 2009-04-08 | 新日本無線株式会社 | 高周波線路の変換器 |
US7449308B2 (en) | 2000-06-28 | 2008-11-11 | Glycofi, Inc. | Combinatorial DNA library for producing modified N-glycans in lower eukaryotes |
DK1296705T3 (da) * | 2000-06-28 | 2012-09-17 | Prana Biotechnology Ltd | Beta-amyloid-oligomerer til anvendelse til behandling, lindring eller forebyggelse af Alzheimers sygdom |
EP2322644A1 (fr) | 2000-06-28 | 2011-05-18 | GlycoFi, Inc. | Procédé de production de glycoprotéines modifiées |
US6686449B2 (en) | 2000-06-30 | 2004-02-03 | Pharmacia & Upjohn Company | Mutant presenilin 1 polypeptides |
EP1297132A1 (fr) | 2000-07-06 | 2003-04-02 | Vlaams Interuniversitair Instituut voor Biotechnologie vzw. | Nouvelle mutation app associee a une pathologie inhabituelle de la maladie d'alzheimer |
AU2007200047B2 (en) | 2000-07-07 | 2009-11-26 | Bioarctic Neuroscience Ab | Prevention and treatment of Alzheimer's disease |
WO2002003911A2 (fr) | 2000-07-07 | 2002-01-17 | Lars Lannfelt | Prevention et traitement de la maladie d'alzheimer |
US6524819B1 (en) | 2000-07-11 | 2003-02-25 | Incyte Genomics, Inc. | Down syndrome critical region 1-like proteins |
EP1172378A1 (fr) | 2000-07-12 | 2002-01-16 | Richard Dr. Dodel | Anticorps humains anti-beta-amyloid et leur utilisation pour le traitement de la maladie d'Alzheimer |
US20020009445A1 (en) | 2000-07-12 | 2002-01-24 | Yansheng Du | Human beta-amyloid antibody and use thereof for treatment of alzheimer's disease |
JP2002040023A (ja) | 2000-07-28 | 2002-02-06 | Mitsubishi Chemicals Corp | アルツハイマー病の検出方法 |
US20070009931A1 (en) | 2000-08-04 | 2007-01-11 | Kirsch Wolff M | Negative correlation between IRP-2 and Transferrin receptor expression as a diagnostic of Alzheimer's disease |
PT1317479E (pt) | 2000-09-06 | 2009-10-29 | Univ Pasteur | Métodos e composições para doenças associadas à amiloidose |
GB0024446D0 (en) | 2000-10-05 | 2000-11-22 | Glaxo Group Ltd | Protein |
IT1319277B1 (it) | 2000-10-24 | 2003-09-26 | Chiesi Farma Spa | Proteine di fusione utili per il trattamento di immunizzazione dellamalattia di alzheimer. |
US6962793B2 (en) | 2000-10-27 | 2005-11-08 | Mount Sinai Hospital | Methods for detecting Alzheimers disease |
WO2002036614A2 (fr) | 2000-11-01 | 2002-05-10 | Insight Biotechnology Limited | Peptides destines a une utilisation dans le traitement de la maladie d'alzheimer |
WO2002094870A2 (fr) | 2000-11-02 | 2002-11-28 | Curagen Corporation | Proteines et acides nucleiques codant pour ces proteines |
DE10055703A1 (de) | 2000-11-02 | 2002-05-08 | Peter F Pascoe | Verhinderung der Zellzerstörung und Beseitigung sklrotischer Amyloide verursacht durch organspezifische Antikörperaggregate |
EP1341548A4 (fr) | 2000-11-03 | 2006-06-14 | Massachusetts Inst Technology | Methodes d'identification de traitements de la neurotoxicite dans la maladie d'alzheimer engendree par des peptides $g(b)-amyloides |
US20060062786A1 (en) | 2000-11-08 | 2006-03-23 | Human Genome Sciences, Inc. | Antibodies that immunospecifically bind to TRAIL receptors |
DE60126980T2 (de) | 2000-11-27 | 2007-11-08 | Praecis Pharmaceuticals Inc., Waltham | Therapeutische agentien und methoden ihrer verwendung zur behandlung von amyloidogenen erkrankungen |
TWI255272B (en) | 2000-12-06 | 2006-05-21 | Guriq Basi | Humanized antibodies that recognize beta amyloid peptide |
GB0100110D0 (en) | 2001-01-04 | 2001-02-14 | Univ Leeds | Modulation of calcium channel activity |
DE10101430B4 (de) | 2001-01-13 | 2008-10-02 | Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. | Lösliche cyclische Analoga zur Modulation der Amyloidogenese |
US20020132758A1 (en) | 2001-01-18 | 2002-09-19 | Shell John W. | Method for identifying compounds to treat medical pathologies associated with molecular crystallization |
US7264810B2 (en) | 2001-01-19 | 2007-09-04 | Cytos Biotechnology Ag | Molecular antigen array |
AT500379B8 (de) | 2001-02-02 | 2009-08-15 | Axon Neuroscience | Tau-proteine |
US7175988B2 (en) | 2001-02-09 | 2007-02-13 | Human Genome Sciences, Inc. | Human G-protein Chemokine Receptor (CCR5) HDGNR10 |
US20040191264A1 (en) | 2001-02-19 | 2004-09-30 | Nielsen Klaus Gregorius | Synthetic vaccine agents |
JP4659236B2 (ja) | 2001-03-01 | 2011-03-30 | 大塚製薬株式会社 | 細胞傷害活性の測定法 |
US6815175B2 (en) | 2001-03-16 | 2004-11-09 | Cornell Research Foundation, Inc. | Anti-amyloid peptide antibody based diagnosis and treatment of a neurological disease or disorder |
FR2822238B1 (fr) | 2001-03-16 | 2003-08-29 | Gemac | Methode et trousse pour le suivi des maladies neurodegeneratives |
DE10117281A1 (de) | 2001-04-06 | 2002-10-24 | Inst Molekulare Biotechnologie | Peptid zur Diagnose und Therapie der Alzheimer-Demenz |
CA2443770A1 (fr) | 2001-04-23 | 2002-10-31 | Curagen Corporation | Proteines et acides nucleiques codant pour celles-ci |
US6451547B1 (en) | 2001-04-25 | 2002-09-17 | Syn X Pharma | Process for differential diagnosis of Alzheimer's dementia and device therefor |
EP1385545B1 (fr) | 2001-04-30 | 2009-01-07 | Eli Lilly And Company | Anticorps humanises reconnaissant le peptide amyloide beta |
US7320790B2 (en) | 2001-04-30 | 2008-01-22 | Eli Lilly And Company | Humanized antibodies |
US7196163B2 (en) | 2001-05-22 | 2007-03-27 | Merk & Co., Inc. | Assays using amyloid precursor proteins with modified β-secretase cleavage sites to monitor β-secretase activity |
EP1395275B1 (fr) | 2001-05-22 | 2008-11-12 | Merck & Co., Inc. | Substrat de beta-secretase et ses utilisations |
US6906169B2 (en) | 2001-05-25 | 2005-06-14 | United Biomedical, Inc. | Immunogenic peptide composition comprising measles virus Fprotein Thelper cell epitope (MUFThl-16) and N-terminus of β-amyloid peptide |
ES2228697T3 (es) | 2001-06-12 | 2005-04-16 | Wiltfang, Jens | Anticuerpo monoclonal, mab 1e8, que es especifico para los dos primeros aminoacidos de peptidos beta-amiloides y su utilizacion en la deteccion de peptidos beta-amiloides y/o sapp alfa. |
US7595378B2 (en) | 2001-06-13 | 2009-09-29 | Genmab A/S | Human monoclonal antibodies to epidermal growth factor receptor (EGFR) |
KR20090125840A (ko) | 2001-06-13 | 2009-12-07 | 젠맵 에이/에스 | 표피 성장 인자 수용체 (egfr)에 대한 인간 모노클로날 항체 |
US7094884B2 (en) | 2001-06-22 | 2006-08-22 | Roche Diagnostics Corporation | Soluble complexes of amylod β peptide and peptidyl prolyl isomerase chaperone and methods of making and using them |
US20020197258A1 (en) | 2001-06-22 | 2002-12-26 | Ghanbari Hossein A. | Compositions and methods for preventing protein aggregation in neurodegenerative diseases |
CN1396183A (zh) | 2001-07-13 | 2003-02-12 | 张小如 | 降低脑内与老年痴呆有关的淀粉样变纤维的融合人抗体 |
WO2003008626A2 (fr) | 2001-07-20 | 2003-01-30 | Oregon Health And Science University | Nouveaux acides nucleiques humains codant pour une pantothenate kinase et procedes d'utilisation |
DE60226036T9 (de) | 2001-08-03 | 2016-09-29 | Medical & Biological Laboratories Co., Ltd. | ANTIKÖRPER, DER DAS GM1-GANGLIOSID-GEBUNDENE AMYLOID-b-PROTEIN ERKENNT, UND DNA, DIE FÜR DIESEN ANTIKÖRPER CODIERT |
JP4320694B2 (ja) | 2001-08-08 | 2009-08-26 | 株式会社オーク製作所 | 多重露光描画装置および多重露光式描画方法 |
WO2003014329A2 (fr) | 2001-08-10 | 2003-02-20 | University Of South Florida | Modulation de l'angiogenese par des peptides a-beta |
DK1944040T3 (da) | 2001-08-17 | 2012-10-29 | Univ Washington | Analysefremgangsmåde for Alzheimers sygdom |
CA2457145C (fr) | 2001-08-17 | 2010-12-21 | Washington University | Procede de dosage destine a la maladie d'alzheimer |
EP1519740A4 (fr) | 2001-08-17 | 2005-11-09 | Lilly Co Eli | Amelioration rapide des processus cognitifs dans les etats pathologiques lies a l'a-beta |
MY144532A (en) | 2001-08-20 | 2011-09-30 | Lundbeck & Co As H | Novel method for down-regulation of amyloid |
US20030082191A1 (en) | 2001-08-29 | 2003-05-01 | Poduslo Joseph F. | Treatment for central nervous system disorders |
EP1438400B1 (fr) | 2001-10-01 | 2009-06-17 | Dyax Corp. | Vecteurs d'affichage eukaryotes multichaine et leurs utilisations |
WO2003028543A2 (fr) | 2001-10-03 | 2003-04-10 | Pfizer Products Inc. | Molecules d'acide nucleique, polypeptides et utilisations associees comprenant le diagnostic et le traitement de la maladie d'alzheimer |
DE60225821T2 (de) | 2001-10-04 | 2009-04-30 | Immuno-Biological Laboratories Co., Ltd., Takasaki | Reagens zum Nachweis eines Risikofaktors der Alzheimer-Krankheit, Nachweiskit dafür und Verfahren zum Nachweis eines Risikofaktors der Alzheimer-Krankheit unter ihrer Verwendung |
US20030099635A1 (en) | 2001-10-04 | 2003-05-29 | Protein Therapeutics, Inc. | Use of oral gammaglobulin for the treatment of immune-mediated diseases |
GB0124317D0 (en) | 2001-10-10 | 2001-11-28 | Celltech R&D Ltd | Biological products |
HUP0600342A3 (en) | 2001-10-25 | 2011-03-28 | Genentech Inc | Glycoprotein compositions |
EP1448601A4 (fr) | 2001-11-02 | 2006-04-26 | Diagenics Internat Corp | Methodes et compositions d'anticorps monoclonaux specifiques des proteines beta-amyloides |
WO2003045128A2 (fr) | 2001-11-21 | 2003-06-05 | New York University | Polypeptides immunogenes synthetiques ne formant pas de depots et peptides homologues destines a des repetitions amyloide $g(b), proteine prion, amyline, $g(a)-synucleine, ou polyglutamine pour induction d'une reponse immunitaire a ceux-ci |
US7179606B2 (en) | 2001-11-23 | 2007-02-20 | Syn X Pharma, Inc. | IG heavy chain, IG kappa, IG lambda biopolymer markers predictive of Alzheimer's disease |
US7026129B2 (en) | 2001-11-23 | 2006-04-11 | Syn X Pharma, Inc. | IG lambda biopolymer markers predictive of Alzheimers disease |
DE10158180A1 (de) | 2001-11-28 | 2003-09-11 | Biovision Ag | Verfahren zum Nachweis von Morbus Alzheimer und zur Unterscheidung von Morbus Alzheimer gegenüber anderen demenziellen Erkrankungen, zugehörige Peptide und deren Verwendung |
AU2002363861A1 (en) | 2001-11-30 | 2003-06-10 | Crucell Holland B.V. | Antigen presenting cell targeting conjugate, an intigen presenting cell contacted with such conjugate, their use for vaccination or as medicament, and methods for their production or generation |
JP2005521645A (ja) | 2001-12-04 | 2005-07-21 | ベン グリオン ユニバーシティ オブ ザ ネジェブ リサーチ アンド ディベラップメント オーソリティ | 器官特異的薬物ターゲティング用両親媒性化合物及び小胞/リポソーム |
WO2003051374A2 (fr) | 2001-12-17 | 2003-06-26 | New York State Office Of Mental Health | SEQUESTRATION DE Aβ DANS LA REGION PERIPHERIQUE EN L'ABSENCE D'AGENTS IMMUNOMODULATEURS COMME APPROCHE THERAPEUTIQUE POUR LE TRAITEMENT OU LA PREVENTION DES MALADIES LIEES A LA BETA-AMYLOIDE |
CA2500462A1 (fr) | 2001-12-26 | 2004-03-25 | Universidad De Zaragoza | Anticorps polyclonaux, methode de preparation et utilisation |
US7781396B2 (en) | 2002-01-31 | 2010-08-24 | Tel Aviv University Future Technology Development L.P. | Peptides directed for diagnosis and treatment of amyloid-associated disease |
US20070021345A1 (en) | 2003-06-30 | 2007-01-25 | Ehud Gazit | Peptides antibodies directed thereagainst and methods using same for diagnosing and treating amyloid-associated diseases |
US20050153381A1 (en) | 2002-02-14 | 2005-07-14 | Marusich Michael F. | Immunocapture of mitochondrial protein complexes |
AR038568A1 (es) | 2002-02-20 | 2005-01-19 | Hoffmann La Roche | Anticuerpos anti-a beta y su uso |
WO2003074004A2 (fr) | 2002-03-01 | 2003-09-12 | Szu-Yi Chou | Procede de production d'antigenes |
KR20040088572A (ko) | 2002-03-01 | 2004-10-16 | 이뮤노메딕스, 인코오포레이티드 | 제거율 증강을 위한 양특이성 항체 점 돌연변이들 |
EP2292247A3 (fr) | 2002-03-05 | 2011-10-05 | Ramot at Tel Aviv University Ltd. | Composition immunisante et procédé permettant d'induire une réponse immunitaire contre le site de clivage de la bêta-sécrétase |
MY139983A (en) | 2002-03-12 | 2009-11-30 | Janssen Alzheimer Immunotherap | Humanized antibodies that recognize beta amyloid peptide |
US8420353B2 (en) | 2002-03-22 | 2013-04-16 | Aprogen, Inc. | Humanized antibody and process for preparing same |
US20030190689A1 (en) | 2002-04-05 | 2003-10-09 | Cell Signaling Technology,Inc. | Molecular profiling of disease and therapeutic response using phospho-specific antibodies |
US7122374B1 (en) | 2002-04-09 | 2006-10-17 | Takaomi Saido | Amyloid beta-protein 3(pE)-42 antibodies and uses thereof |
WO2003086310A2 (fr) | 2002-04-12 | 2003-10-23 | Ramot At Tel Aviv University Ltd. | Prevention de l'inflammation du cerveau en tant que resultat d'une reponse auto-immune induite |
PL209696B1 (pl) | 2002-04-19 | 2011-10-31 | Univ Toronto | Peptyd, kompozycja peptydowa, kompozycja immunogenna, zastosowania kompozycji immunogennej oraz sposób określania czy związek stanowi inhbitor odkładania się i tworzenia włókienek amyloidu |
WO2003091734A1 (fr) | 2002-04-24 | 2003-11-06 | Evotec Neurosciences Gmbh | Utilisation a des fins diagnostiques et therapeutiques du gene et de la proteine ensadine-0477 pour le traitement de maladies neurodegeneratives |
JP2005523335A (ja) | 2002-04-25 | 2005-08-04 | イーライ・リリー・アンド・カンパニー | 高齢被検体の不安障害および気分障害の治療方法 |
US20060257420A1 (en) | 2002-04-26 | 2006-11-16 | Cel-Sci Corporation | Methods of preparation and composition of peptide constructs useful for treatment of autoimmune and transplant related host versus graft conditions |
DE10221052A1 (de) | 2002-05-10 | 2003-12-04 | Transmit Technologietransfer | Wirkstoffe zu Therapie, Diagnostik und Prophylaxe von Erkrankungen, bei denen abnorme Proteinstrukturen auftreten |
WO2003100419A1 (fr) | 2002-05-27 | 2003-12-04 | Bioceros B.V. | Procedes d'utilisation de la voie de cd163 pour moduler une reponse immunitaire |
AU2003241131A1 (en) | 2002-06-14 | 2003-12-31 | Brainsgate Ltd. | Methods and systems for management of alzheimer's disease |
AU2003278497A1 (en) | 2002-06-20 | 2004-01-06 | Evotec Neurosciences Gmbh | Diagnostic and therapeutic use of ras-gtpase-activating sh3-domain-binding protein 2 (g3bp2) for neurodegenerative diseases |
WO2004003563A2 (fr) | 2002-06-27 | 2004-01-08 | Evotec Neurosciences Gmbh | Utilisation diagnostique et therapeutique de la proteine et du gene ensadin-0581 dans le cadre des maladies neurodegeneratives |
ATE328906T1 (de) | 2002-06-28 | 2006-06-15 | Domantis Ltd | Dual-specifische liganden mit erhöhter halbwertszeit |
DK1521831T3 (da) | 2002-07-12 | 2008-06-30 | Axon Neuroscience | Transgent dyr der udtrykker trunkeret alzheimers tauprotein |
AU2003256578A1 (en) | 2002-07-17 | 2004-02-02 | Intellect Neurosciences, Inc. | Peptides and methods of screening immunogenic peptide vaccines against alzheimer's disease |
EP1544210A4 (fr) | 2002-07-18 | 2006-01-25 | Masayasu Okochi | Nouveaux polypeptides d'origine notch, biomarqueurs et reactifs faisant appel a ces derniers |
NZ598346A (en) | 2002-07-19 | 2013-10-25 | Abbvie Biotechnology Ltd | Treatment of tnf alpha related disorders |
KR101070078B1 (ko) | 2002-07-19 | 2011-10-04 | 노파르티스 파르마 아게 | 아밀로이드 베타1-6 항원 어레이를 포함하는 백신 조성물 |
EP1523499A2 (fr) | 2002-07-24 | 2005-04-20 | Innogenetics N.V. | Fragments du peptide beta-amyloide en tant que cibles pour la vaccination contre la maladie d'alzheimer |
US7250551B2 (en) | 2002-07-24 | 2007-07-31 | President And Fellows Of Harvard College | Transgenic mice expressing inducible human p25 |
SE0202880D0 (sv) | 2002-07-26 | 2002-09-30 | Wieslab Ab | Complement system deficiency assay |
EP1543331B1 (fr) | 2002-07-30 | 2009-02-11 | The J. David Gladstone Institutes | Procede de diagnostic de la maladie d'alzheimer |
US20040138296A1 (en) | 2002-08-12 | 2004-07-15 | Pharmacia Corporation | Amyloid immunization and Cox-2 inhibitors for the treatment of alzheimer's disease |
US7252953B2 (en) | 2002-08-13 | 2007-08-07 | United States Of America Department Of Veterans Affairs | Method of detecting and preventing Alzheimer's disease, particularly at prodromal and early stages |
WO2004016655A1 (fr) | 2002-08-14 | 2004-02-26 | Mitsubishi Chemical Corporation | Anticorps specifique a une proteine-$g(t) centrale |
AU2003259965A1 (en) | 2002-08-20 | 2004-03-11 | Neurogenetics, Inc. | Methods and compositions for modulating amyloid beta |
AU2003266302A1 (en) | 2002-08-23 | 2004-03-11 | Proteosys Ag | Method for the diagnosis of alzheimer disease |
AU2003270643A1 (en) | 2002-09-12 | 2004-04-30 | The Regents Of The University Of California | Immunogens and corresponding antibodies specific for high molecular weight aggregation intermediates common to amyloids formed from proteins of differing sequence |
US7238488B2 (en) | 2002-09-13 | 2007-07-03 | Grace Maresh | Therapeutic and diagnostic applications of perlecan domain I splice variants |
US20070010657A1 (en) | 2002-09-13 | 2007-01-11 | Rainer Klocke | Cytoplasmic dynein heavy chain 1 genes, expression products, non-human animal model uses in human neurological diseases |
US20040127471A1 (en) | 2002-09-17 | 2004-07-01 | Barry Reisberg | Methods of treating age associated memory impairment (AAMI), mild cognitive impairment (MCI), and dementias with cell cycle inhibitors |
JP4242128B2 (ja) | 2002-09-18 | 2009-03-18 | 武田薬品工業株式会社 | 脳アミロイドーシス予防・治療薬のスクリーニング方法 |
WO2004029629A1 (fr) | 2002-09-27 | 2004-04-08 | Janssen Pharmaceutica N.V. | Anticorps monoclonaux beta-amyloide n-11 tronques, compositions, methodes et utilisations |
US7541440B2 (en) | 2002-09-30 | 2009-06-02 | Immunomedics, Inc. | Chimeric, human and humanized anti-granulocyte antibodies and methods of use |
JP2006508072A (ja) * | 2002-10-01 | 2006-03-09 | ノースウエスタン ユニバーシティ | アミロイドベータ由来拡散性リガンド(ADDLs)、ADDL代替物、ADDL結合性分子、およびそれらの使用 |
US20070213512A1 (en) | 2002-10-01 | 2007-09-13 | Krafft Grant A | Amyloid beta peptide analogs and assemblies thereof |
AU2003272925A1 (en) | 2002-10-04 | 2004-04-23 | Techno Network Shikoku Co., Ltd. | Monoclonal antibody against subtilisin-like proprotein convertase pace4 and utilization thereof |
JP2006514824A (ja) | 2002-10-09 | 2006-05-18 | アクティブクス バイオサイエンスィズ インコーポレイテッド | 活性に基づくプローブ,およびその製造および使用方法 |
PL377769A1 (pl) | 2002-10-09 | 2006-02-20 | Rinat Neuroscience Corp. | Sposób leczenia choroby Alzheimera z zastosowaniem przeciwciał skierowanych przeciw peptydowi beta amyloidu i ich kompozycje |
AU2003279312A1 (en) | 2002-10-24 | 2004-05-13 | Evotec Neurosciences Gmbh | Diagnostic and therapeutic use of ensadin-0289 gene and protein for neurodegenerative diseases |
US20080014194A1 (en) | 2003-10-31 | 2008-01-17 | Elan Pharmaceuticals, Inc. | Prevention and Treatment of Synucleinopathic and Amyloidogenic Disease |
TW200509968A (en) | 2002-11-01 | 2005-03-16 | Elan Pharm Inc | Prevention and treatment of synucleinopathic disease |
FR2846667B1 (fr) | 2002-11-06 | 2004-12-31 | Pasteur Institut | Fragments variables d'anticorps de camelides a chaine unique diriges contre le peptide beta-amyloide 1-42 et leurs applications pour le diagnostic et le traitement des maladies neuroagregatives |
WO2004043989A2 (fr) | 2002-11-07 | 2004-05-27 | Medarex, Inc. | Anticorps monoclonaux humains diriges contre l'heparanase |
WO2004045525A2 (fr) | 2002-11-15 | 2004-06-03 | Morehouse School Of Medicine | Anticorps anti-chimiokines et anticorps anti-recepteurs associes et utilisations de ces anticorps pour inhiber des inflammations |
CN100450551C (zh) | 2002-11-29 | 2009-01-14 | 中国医学科学院基础医学研究所 | 用于治疗和预防阿尔茨海默病的重组腺相关病毒基因疫苗及其用途 |
DE10256900A1 (de) | 2002-11-29 | 2004-06-24 | Nemod Immuntherapie Ag | Tumorspezifische Erkennungsmoleküle |
CN1878795A (zh) | 2002-12-02 | 2006-12-13 | 阿布格尼克斯公司 | 针对磷脂酶a2的抗体及其应用 |
WO2004056318A2 (fr) | 2002-12-19 | 2004-07-08 | New York University | Methode permettant de traiter une maladie amyloide |
WO2004058239A1 (fr) | 2002-12-24 | 2004-07-15 | Neurochem (International) Limited | Formulations therapeutiques destinees au traitement de maladies liees au peptide beta-amyloide |
US20050031651A1 (en) | 2002-12-24 | 2005-02-10 | Francine Gervais | Therapeutic formulations for the treatment of beta-amyloid related diseases |
GB0230203D0 (en) | 2002-12-27 | 2003-02-05 | Domantis Ltd | Fc fusion |
AT413945B (de) | 2003-01-14 | 2006-07-15 | Mattner Frank Dr | Impfstoff für die alzheimer-krankheit |
CA2514153A1 (fr) | 2003-01-22 | 2004-08-05 | Takeda Pharmaceutical Company Limited | Anticorps et utilisation de ce dernier |
WO2004065569A2 (fr) | 2003-01-23 | 2004-08-05 | The Regents Of The University Of California | Anticorps multifonctionnels |
US7563869B2 (en) | 2003-01-23 | 2009-07-21 | Ono Pharmaceutical Co., Ltd. | Substance specific to human PD-1 |
DE10303974A1 (de) * | 2003-01-31 | 2004-08-05 | Abbott Gmbh & Co. Kg | Amyloid-β(1-42)-Oligomere, Verfahren zu deren Herstellung und deren Verwendung |
PL378571A1 (pl) | 2003-02-01 | 2006-05-02 | Neuralab Limited | Czynna immunizacja dla wytworzenia przeciwciał przeciw rozpuszczalnemu A-ß |
US7223393B2 (en) | 2003-02-07 | 2007-05-29 | Pdl Biopharma, Inc | Amphiregulin antibodies and their use to treat cancer and psoriasis |
EP1596809B1 (fr) | 2003-02-10 | 2010-05-26 | Applied Molecular Evolution, Inc. | Molecules de liaison au peptide abeta |
US20040242845A1 (en) | 2003-02-21 | 2004-12-02 | Nicolau Yves Claude | Methods and compositions comprising supramolecular antigenic constructs and antibodies elicited against them |
US8663650B2 (en) | 2003-02-21 | 2014-03-04 | Ac Immune Sa | Methods and compositions comprising supramolecular constructs |
US20060188951A1 (en) | 2003-02-24 | 2006-08-24 | In Hee Mook | Method for measuring the level of anti-beta-amyloid antibody in body fluids and diagnostic kit for alzheimer's disease using same |
US20040223970A1 (en) | 2003-02-28 | 2004-11-11 | Daniel Afar | Antibodies against SLC15A2 and uses thereof |
US20060104968A1 (en) | 2003-03-05 | 2006-05-18 | Halozyme, Inc. | Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminogly ycanases |
DK2163643T3 (en) | 2003-03-05 | 2015-03-23 | Halozyme Inc | Soluble hyaluronidaseglycoprotein (sHASEGP), process for preparing the same, pharmaceutical compositions and uses thereof covered |
WO2004085712A2 (fr) | 2003-03-24 | 2004-10-07 | Penn State Research Foundation | Materiaux polymeres multifonctionnels et leurs utilisations |
JP4939929B2 (ja) | 2003-03-26 | 2012-05-30 | ポール,サッドヒル | タンパク質分解抗体および共有結合抗体 |
CN1189210C (zh) | 2003-03-28 | 2005-02-16 | 万选才 | Cb与生物活性多肽的偶联物及其医药用途 |
AU2004274390A1 (en) | 2003-03-28 | 2005-03-31 | Jacqueline M. Benson | Anti-amyloid antibodies, compositions, methods and uses |
US7632816B2 (en) | 2003-03-28 | 2009-12-15 | New York University | Treatment of Alzheimer amyloid deposition |
CA2522067C (fr) | 2003-04-09 | 2010-07-06 | Canadian Blood Services | Detection, caracterisation et traitement d'infections virales, et procedes associes |
EP1469312A1 (fr) | 2003-04-18 | 2004-10-20 | Friedrich-Alexander-Universität Erlangen-Nürnberg | Le diagnostic de la maladie d'Alzheimer |
US20060240485A1 (en) | 2003-04-24 | 2006-10-26 | Universitat Zurich | Method of monitoring immunotherapy |
CA2524737A1 (fr) | 2003-05-06 | 2005-02-24 | Human Genome Sciences, Inc. | Anticorps se liant de maniere immunospecifique aux recepteurs trail |
US20040223912A1 (en) | 2003-05-07 | 2004-11-11 | Montalto Michael Christopher | Compositions and methods for non-invasive imaging of soluble beta-amyloid |
ES2246178B1 (es) | 2003-05-08 | 2007-03-01 | Universidad De Zaragoza. | Uso de anticuerpos para el tratamiento de enfermedades amiloideas. |
EP1480041A1 (fr) | 2003-05-22 | 2004-11-24 | Innogenetics N.V. | Méthode de prédiction, diagnostic et diagnostic différential de la maladie d'Alzheimer |
WO2005018536A2 (fr) | 2003-05-23 | 2005-03-03 | Human Genome Sciences, Inc. | Anticorps agonistes de liaison specifique au recepteur de peptide 1 assimile au glucagon |
PE20050627A1 (es) | 2003-05-30 | 2005-08-10 | Wyeth Corp | Anticuerpos humanizados que reconocen el peptido beta amiloideo |
CA2528182A1 (fr) | 2003-06-06 | 2005-06-16 | Oncomax Acquisition Corp. | Anticorps specifiques de l'antigene sm5-1 associe au cancer et utilisations associees |
US7892751B2 (en) | 2003-06-09 | 2011-02-22 | Redox-Reactive Reagents Llc | Method of detecting or diagnosing of a neurodegenerative disease or condition |
JP4888876B2 (ja) | 2003-06-13 | 2012-02-29 | 田平 武 | アルツハイマー病の治療のための組換えアデノ随伴ウィルスベクター |
KR20060022289A (ko) | 2003-06-23 | 2006-03-09 | 제네틱스 인스티튜트, 엘엘씨 | 인터류킨-22 에 대한 항체 및 그의 용도 |
US20050009110A1 (en) | 2003-07-08 | 2005-01-13 | Xiao-Jia Chang | Methods of producing antibodies for diagnostics and therapeutics |
JP4788999B2 (ja) | 2003-07-15 | 2011-10-05 | 小野薬品工業株式会社 | 分枝鎖カルボン酸化合物およびその用途 |
WO2005012330A2 (fr) | 2003-07-30 | 2005-02-10 | Brigham And Women's Hospital, Inc. | Peptide $g(b)-amyloide et procedes pour l'utiliser |
WO2005011599A2 (fr) | 2003-08-01 | 2005-02-10 | Northwestern University | Anticorps specifiques des oligomeres a proteines beta amyloides toxiques |
WO2005014618A2 (fr) | 2003-08-08 | 2005-02-17 | Immunomedics, Inc. | Anticorps bispecifiques pour induire l'apoptose de cellules tumorales et malades |
JP4239750B2 (ja) | 2003-08-13 | 2009-03-18 | セイコーエプソン株式会社 | マイクロレンズ及びマイクロレンズの製造方法、光学装置、光伝送装置、レーザプリンタ用ヘッド、並びにレーザプリンタ |
WO2005018424A2 (fr) | 2003-08-18 | 2005-03-03 | Research Foundation For Mental Hygiene, Inc. | Anticorps specifiques de la proteine amyloide fibrillaire et procedure permettant de detecter des depots de proteines amyloides fibrillaires |
US20050042664A1 (en) | 2003-08-22 | 2005-02-24 | Medimmune, Inc. | Humanization of antibodies |
US20070031416A1 (en) | 2003-09-09 | 2007-02-08 | Takeda Pharmaceutical Company Limited | Use of antibody |
US20070110750A1 (en) | 2003-09-12 | 2007-05-17 | The Regents Of The University Of California | Monoclonal antibodies specific for high molecular weight aggregation intermediates common to amyloids formed from proteins of differing sequence |
EP1516930A1 (fr) | 2003-09-16 | 2005-03-23 | Georg-August Universität Göttingen | Modèle cellulaire des tauopathies pour identifier "lead" et découvrir des médicaments |
EP1670510A1 (fr) | 2003-09-24 | 2006-06-21 | Peter Krammer | Anticorps diriges contre les annexines, leur utilisation a des fins therapeutiques et diagnostiques, utilisation des annexines a des fins therapeutiques et diagnostiques |
IL158287A0 (en) | 2003-10-07 | 2004-05-12 | Yeda Res & Dev | Antibodies to nik, their preparation and use |
AU2004278175B2 (en) | 2003-10-07 | 2010-11-04 | Yeda Research And Development Co. Ltd. | Antibodies to NIK, their preparation and use |
US20070015218A1 (en) | 2003-10-14 | 2007-01-18 | University Of South Florida | A Method for the Separation Anti-Amyloid Beta Antibody with Amyloid Beta Peptide |
EP2071333B1 (fr) | 2003-10-15 | 2012-04-18 | Sekisui Medical Co., Ltd. | Procédé d'analyse sélective de multimers d'adiponectine |
CA2543058A1 (fr) | 2003-10-20 | 2005-05-12 | Envivo Pharmaceuticals, Inc. | Mouches transgeniques exprimant un mutant a.beta.42 |
JP2007535906A (ja) | 2003-10-24 | 2007-12-13 | イステイチユート・デイ・リチエルケ・デイ・ビオロジア・モレコラーレ・ピ・アンジエレツテイ・エツセ・ピー・アー | 直交遺伝子スイッチ |
PT1682180E (pt) | 2003-11-04 | 2010-02-10 | Novartis Vaccines & Diagnostic | Anticorpos monoclonais antagonistas anti-cd40 e métodos para a sua utilização |
US7807777B2 (en) | 2003-11-05 | 2010-10-05 | Immuno-Biological Laboratories Co., Ltd. | Marker peptide for alzheimer's disease |
EP1694816B1 (fr) | 2003-11-07 | 2013-08-28 | Ciphergen Biosystems, Inc. | Biomarqueurs pour la maladie d'alzheimer |
US20070264280A1 (en) | 2003-11-07 | 2007-11-15 | Federoff Howard J | Compositions and Methods for Treating Neurological Diseases |
US7674599B2 (en) | 2003-11-08 | 2010-03-09 | Elan Pharmaceuticals, Inc. | Methods of using antibodies to detect alpha-synuclein in fluid samples |
KR100556660B1 (ko) | 2003-11-11 | 2006-03-10 | 국립암센터 | Hgf의 중화가능 에피토프 및 이에 결합하는 중화 항체 |
US20050226863A1 (en) | 2003-11-20 | 2005-10-13 | Massachusetts Institute Of Technology | Single-domain antibodies and uses thereof |
WO2005051998A2 (fr) | 2003-11-28 | 2005-06-09 | Astrazeneca Ab | Anticorps |
JP4870348B2 (ja) | 2003-12-04 | 2012-02-08 | 株式会社ペルセウスプロテオミクス | 細胞表面抗原に対する抗体取得とその抗原同定 |
EP2865687A1 (fr) | 2003-12-10 | 2015-04-29 | E. R. Squibb & Sons, L.L.C. | Anticorps IP-10 et leurs utilisations |
UA93854C2 (ru) | 2003-12-17 | 2011-03-25 | Вайет Ллк | Иммуногенный конъюгат и способ его получения |
BRPI0417959A (pt) | 2003-12-22 | 2007-03-27 | Glaxo Group Ltd | anticorpo ou fragmento funcional deste, composição farmcêutica, método para tratamento ou profilaxia de acidente vascular cerebral e outras doenças/distúrbios neurológicos em um ser humano, uso de um anticorpo anti-nogo, e, métodos para inibir a neurodegeneração e/ou promover a recuperação funcional em um paciente humano, para promover o crescimento axonal, para produzir um anticorpo anti-nogo e para produzir uma composição farmacêutica intravenosamente administrável |
WO2005070965A2 (fr) | 2004-01-21 | 2005-08-04 | Five Prime Therapeutics, Inc. | Compositions pharmaceutiques contenant des antagonistes a lrp4, lrp8 ou a la megaline pour le traitement de maladies |
US20070172496A1 (en) | 2004-01-28 | 2007-07-26 | Curix Aps | Conjugates of amyloid proteins as vaccines for amyloid-related diseases |
US7238788B2 (en) | 2004-02-18 | 2007-07-03 | University Of Iowa Foundation | Antibodies to phosphorylated tau, methods of making and methods of use |
US7807157B2 (en) | 2004-02-20 | 2010-10-05 | Intellect Neurosciences Inc. | Monoclonal antibodies and use thereof |
US20070190046A1 (en) | 2004-02-23 | 2007-08-16 | Eli Lilly And Company | Anti-abeta antibody |
WO2005105841A2 (fr) | 2004-03-12 | 2005-11-10 | Human Genome Sciences, Inc. | Récepteur humain (ccr5) hdgnr10 de chimiokine de la protéine g |
US20080057057A1 (en) | 2004-03-18 | 2008-03-06 | Applied Research Systems Ars Holding N.V. | Anti-Lipid Rafts Antibodies |
CN1314805C (zh) | 2004-03-26 | 2007-05-09 | 中国人民解放军军事医学科学院放射与辐射医学研究所 | 一种新型促细胞凋亡素(apo)及其抗体,制备及用途 |
SI1730191T1 (sl) | 2004-03-30 | 2011-11-30 | Glaxo Group Ltd | Imunoglobulin-vezavni hOSM |
JP2008502880A (ja) | 2004-04-02 | 2008-01-31 | メルク エンド カムパニー インコーポレーテッド | アミロイド前駆体タンパク質又はβアミロイド断片に結合する物質を検出する方法及び結合化合物 |
US20060099211A1 (en) | 2004-04-12 | 2006-05-11 | Carmen Monthe | Safer, more potent human immunoglobulin preparations for treating Alzheimer's disease |
JP2007535317A (ja) | 2004-04-15 | 2007-12-06 | グライコフィ, インコーポレイテッド | 下等真核生物におけるガラクトシル化された糖タンパク質の産生 |
EP1755605A2 (fr) | 2004-04-15 | 2007-02-28 | Samaritan Pharmaceuticals, Inc. | Utilisation des (2-alkylpiperazinyl) (phenyl) methanones dans le traitement de la maladie d'alzheimer |
US7763249B2 (en) | 2004-04-27 | 2010-07-27 | Juridical Foundation The Chemo-Sero-Therapeutic Research Institute | Human anti-amyloid β peptide antibody and fragment of said antibody |
ITRM20040212A1 (it) | 2004-04-30 | 2004-07-30 | Lay Line Genomics Spa | Animale transgenico non umano come modello per malattie neurodegenerative e per la loro diagnosi precoce. |
GR1005016B (el) | 2004-05-14 | 2005-10-11 | BIOMENTIKA@ΛΑΙΦ@ΣΑΙΕΝΣΙΣ@ΑΝΩΝΥΜΗ@ΕΤΑΙΡΕΙΑ@ΦΑΡΜΑΚΕΥΑΤΙΚΩΝ@ΠΡΟΙΟΝΤΩΝ@(συμμετέχει@σε@ποσοστό@50%)@Α | ΑΝΑΠΤΥΞΗ ΑΝΤΙΣΩΜΑΤΩΝ IgG KAI IgY ΕΝΑΝΤΙΟΝ ΕΙΔΙΚΟΥ ΣΥΝΘΕΤΙΚΟΥ ΕΠΙΤΟΠΙΚΟΥ ΠΑΡΑΓΩΓΟΥ ΤΗΣ HUMANIN (24-ΠΕΠΤΙΔΙΟΥ ΣΧΕΤΙΖΟΜΕΝΟΥ ΜΕ ΤΗ ΝΟΣΟ ALZHEIMER) ΙΚΑΝΩΝ ΝΑ ΑΝΙΧΝΕΥΟΥΝ ΤΟ ΒΙΟΔΡΑΣΤΙΚΟ 24-ΠΕΠΤΙΔΙΟ. |
JP2008500286A (ja) | 2004-05-14 | 2008-01-10 | ノースウエスタン ユニバーシティ | Addl受容体を含む組成物、関連する組成物、および関連する方法 |
ATE476993T1 (de) | 2004-06-07 | 2010-08-15 | Univ Ramot | Verfahren zur passiven immunisierung gegen eine durch amyloidaggregation gekennzeichnete krankheit oder erkrankung mit vermindertem nervenentzündungsrisiko |
WO2005123776A1 (fr) | 2004-06-10 | 2005-12-29 | Omeros Corporation | Procédés servant à traiter des affections associées à l'activation du complément dépendant de la lectine |
US20050276806A1 (en) | 2004-06-15 | 2005-12-15 | Advanced Biotherapy, Inc. | Treatment of autism |
EP1877082A2 (fr) | 2004-06-18 | 2008-01-16 | The Government of the United States of America as represented by The Secretary of the Department of Health and Human Services | Preparation des globulines anti-lymphocytic et anti-monocytic pour empecher des immuno-reactions |
SE0401601D0 (sv) | 2004-06-21 | 2004-06-21 | Bioarctic Neuroscience Ab | Protofibril specific antibodies and uses thereof |
JP2008513732A (ja) | 2004-07-02 | 2008-05-01 | ノースウエスタン ユニバーシティ | アミロイドβ(Abeta)の病理学的なアセンブリを標的とするモノクローナル抗体 |
WO2006005588A1 (fr) | 2004-07-12 | 2006-01-19 | Geneprot, Inc. | Especes de polypeptide convenant pour le traitement de troubles neurologiques |
AT413946B (de) | 2004-07-13 | 2006-07-15 | Mattner Frank Dr | Impfstoff gegen die alzheimer-krankheit |
CN1721437A (zh) | 2004-07-13 | 2006-01-18 | 中南大学 | 一种与Tau蛋白相关的多肽抗原及抗体 |
AT500483B1 (de) | 2004-07-13 | 2006-01-15 | Mattner Frank Dr | Set zur vorbeugung oder behandlung der alzheimer'schen erkrankung |
WO2006006172A2 (fr) | 2004-07-15 | 2006-01-19 | Ramot At Tel Aviv University Ltd. | Utilisation d'agents anti-amyloides pour traiter et determiner des infections pathogenes |
US7955812B2 (en) | 2004-07-19 | 2011-06-07 | The General Hospital Corporation | Methods of diagnosing alzheimer's disease by detecting antibodies to cross-linked β-amyloid oligomers |
MX2007001102A (es) | 2004-07-28 | 2007-04-13 | Schering Corp | Inhibidores macrociclicos de beta-secretasa. |
SG190665A1 (en) | 2004-07-30 | 2013-06-28 | Rinat Neuroscience Corp | Antibodies directed against amyloid-beta peptide and methods using same |
US20070298029A1 (en) | 2004-08-09 | 2007-12-27 | Carsten Hopf | Treatment of Neurodegenerative Diseases by the Use of Degs Inhibitors |
JP2008508893A (ja) | 2004-08-11 | 2008-03-27 | エボテツク・ニユーロサイエンシーズ・ゲー・エム・ベー・ハー | 形質膜atpアーゼの診断及び治療への使用 |
EP1787998A4 (fr) | 2004-08-11 | 2008-08-27 | Mitsubishi Chem Corp | Anticorps et utilisation s'y rapportant |
DE102004039326A1 (de) | 2004-08-12 | 2006-02-16 | Abbott Gmbh & Co. Kg | Neue medizinische Verwendungen und Verfahren |
US7335491B2 (en) | 2004-08-27 | 2008-02-26 | Wyeth Research Ireland Limited | Production of anti-abeta |
US20060246075A1 (en) | 2004-09-29 | 2006-11-02 | Marc Mercken | Anti-amyloid antibodies, compositions, methods and uses |
WO2006039327A2 (fr) | 2004-10-01 | 2006-04-13 | Merck & Co., Inc. | Procedes de traitement ou prophylaxie de maladies amyloidogeniques de l'oeil ou du nerf optique |
US7910100B2 (en) | 2004-10-01 | 2011-03-22 | Max-Planck-Gesellschaft zur Forderung der Wissen | Antibodies directed to the mammalian EAG1 ion channel protein |
EA200700751A1 (ru) | 2004-10-05 | 2008-06-30 | Элан Фарма Интернэшнл Лимитед | Способы и композиции для улучшения продуцирования рекомбинантного белка |
ZA200702869B (en) | 2004-10-06 | 2008-07-30 | Mori Hiroshi | Mutated amyloid protein |
JP5113523B2 (ja) | 2004-10-13 | 2013-01-09 | アブリンクス ナームローゼ フェンノートシャップ | アミロイド−βに対するナノ抗体及びアルツハイマー病のような神経変性疾患の治療のためのナノ抗体TMを含むポリペプチド |
WO2006047254A1 (fr) | 2004-10-22 | 2006-05-04 | Regents Of The University Of Minnesota | Ensembles de proteines beta-amyloides oligomeres et utilisations de ceux-ci |
EP2465872A3 (fr) | 2004-10-25 | 2012-12-19 | Merck Sharp & Dohme Corporation | Anticorps anti-ADDL et leurs utilisations |
WO2006047670A2 (fr) | 2004-10-26 | 2006-05-04 | Wyeth | Procedes permettant d'evaluer les anticorps diriges contre des antigenes associes aux maladies neurodegeneratives |
WO2006050041A2 (fr) | 2004-10-28 | 2006-05-11 | Ramot At Tel Aviv University Ltd. | Procedes pour reduire ou inhiber une inflammation cerebrale ou pour promouvoir une neurogenese |
CA2585148A1 (fr) | 2004-10-28 | 2006-05-04 | Sanko Junyaku Co., Ltd. | Procede d'examen de la maladie d'alzheimer et reactif de diagnostic |
JP2008519284A (ja) | 2004-11-08 | 2008-06-05 | ナノバック ファーマシューティカルズ, インコーポレイテッド | タンパク質−ヒドロキシアパタイト複合体に関する方法および組成物、ならびにカルシウム結合タンパク質−ヒドロキシアパタイト複合体に対する抗体の検出のための新規インビトロ試験を含む免疫系を試験および調節することにおけるそれらの適用 |
US7709208B2 (en) | 2004-11-08 | 2010-05-04 | New York University | Methods for diagnosis of major depressive disorder |
CN1772766A (zh) | 2004-11-12 | 2006-05-17 | 中国科学院上海生命科学研究院 | 抗细胞凋亡相关乙酰胆碱酯酶单克隆抗体及其用途 |
EP2186518A1 (fr) | 2004-11-17 | 2010-05-19 | McLaurin, Joanne | Préparations comprenant des dérivés de scyllo-inositol et méthodes de traitement de troubles d'agrégation protéinique |
US8916165B2 (en) | 2004-12-15 | 2014-12-23 | Janssen Alzheimer Immunotherapy | Humanized Aβ antibodies for use in improving cognition |
US7625560B2 (en) | 2004-12-15 | 2009-12-01 | Janssen Alzheimer Immunotherapy | Humanized antibodies that recognize beta amyloid peptide |
WO2006066118A2 (fr) | 2004-12-15 | 2006-06-22 | Neuralab Limited | Conditionnement contextuel des peurs pour predire l'efficacite immunotherapeutique |
US20060240486A1 (en) | 2004-12-15 | 2006-10-26 | Johnson-Wood Kelly L | Immunoprecipitation-based assay for predicting in vivo efficacy of beta-amyloid antibodies |
PE20061401A1 (es) | 2004-12-15 | 2006-12-23 | Neuralab Ltd | ANTICUERPOS Aß PARA MEJORAR LA COGNICION |
JP2006166879A (ja) | 2004-12-20 | 2006-06-29 | Japan Health Science Foundation | Ab−dip、並びにアルツハイマー病の予防及び治療剤 |
MY146381A (en) | 2004-12-22 | 2012-08-15 | Amgen Inc | Compositions and methods relating relating to anti-igf-1 receptor antibodies |
WO2006067792A2 (fr) | 2004-12-22 | 2006-06-29 | Yeda Research And Development Co. Ltd. At The Weizmann Institute Of Science | Autoantigenes de l'aldolase utiles pour le diagnostic et le traitement de la maladie d'alzheimer |
EP1827493A4 (fr) | 2004-12-22 | 2009-09-30 | Univ St Louis | Utilisation d'anticorps anti-abeta pour le traitement d'un traumatisme cerebral |
EP1676859A1 (fr) | 2004-12-30 | 2006-07-05 | Pevion Biotech Ltd. | Compositions immunogènes contenant des peptides cycliques derivés du peptide beta-amyloide |
US20110020237A1 (en) | 2005-01-14 | 2011-01-27 | Glabe Charles G | Compositions and Methods for Inhibiting Drusen Formation and for Diagnosing or Treating Drusen-Related Disorders |
AU2006208226A1 (en) | 2005-01-24 | 2006-08-03 | Amgen Inc. | Humanized anti-amyloid antibody |
GT200600031A (es) | 2005-01-28 | 2006-08-29 | Formulacion anticuerpo anti a beta | |
JP2006213621A (ja) | 2005-02-02 | 2006-08-17 | Japan Health Science Foundation | Adoplinタンパク質、およびその利用 |
US20070082350A1 (en) | 2005-02-09 | 2007-04-12 | Philip Landfield | Assay and method for diagnosing and treating alzheimer's disease |
US7700099B2 (en) | 2005-02-14 | 2010-04-20 | Merck & Co., Inc. | Non-immunostimulatory antibody and compositions containing the same |
US7731962B2 (en) | 2005-02-14 | 2010-06-08 | Merck & Co., Inc. | Anti-ADDL monoclonal antibody and use thereof |
GB0503434D0 (en) | 2005-02-18 | 2005-03-30 | Senexis Ltd | Amyloid-binding peptides, analogues and uses thereof |
BRPI0607486B8 (pt) | 2005-03-03 | 2021-05-25 | Immunomedics Inc | anticorpo humanizado l243 contra hla-dr presente nas células hladr+,composição farmacêutica, kit e uso dos referidos anticorpos. |
CN101171263A (zh) | 2005-03-04 | 2008-04-30 | 比奥根艾迪克Ma公司 | 通过合理修饰互补决定区残基使免疫球蛋白可变区人源化的方法 |
EP1861422B1 (fr) | 2005-03-05 | 2010-02-24 | Abbott GmbH & Co. KG | Methode de criblage, procede servant a purifier des a-beta oligomeres non diffusibles, anticorps selectifs contre les dits a-beta oligomeres non diffusibles et procede servant a preparer ces anticorps |
US20080152644A1 (en) | 2005-03-07 | 2008-06-26 | Ho-Juhn Song | Genes Involved in Neurodegenerative Conditions |
ES2259270B1 (es) | 2005-03-09 | 2007-11-01 | Consejo Superior De Investigaciones Cientificas | Metodo de diagnostico in vitro de la enfermedad de alzheimer mediante un anticuerpo monoclonal. |
WO2006099543A2 (fr) | 2005-03-15 | 2006-09-21 | The Regents Of The University Of California | Methodes d'evaluation de la toxicite induite par des anticorps |
WO2006100679A2 (fr) | 2005-03-22 | 2006-09-28 | Quark Pharmaceuticals, Inc. | Anticorps de recombinaison diriges contre la transglutaminase humaine de type ii et utilisations de ces anticorps |
JP2006265189A (ja) | 2005-03-24 | 2006-10-05 | Kyoto Univ | βアミロイドペプチド、及びそれを用いたアルツハイマー病治療薬又は予防薬のスクリーニング方法 |
ES2318918B1 (es) | 2005-04-01 | 2010-02-16 | Biotherapix Molecular Medicines, S.L.U. | Anticuerpos humanos con capacidad de union al peptido beta-amiloide y sus aplicaciones. |
US8227194B2 (en) | 2005-04-08 | 2012-07-24 | University Of Maryland, Baltimore | Monoclonal antibodies with binding specificity for response gene to complement 32 (RGC-32) |
US20060241038A1 (en) | 2005-04-20 | 2006-10-26 | Eisai Co., Ltd. | Therapeutic agent for Abeta related disorders |
ZA200708857B (en) | 2005-04-22 | 2009-01-28 | Genentech Inc | Method for treating dementia or alzheimer's disease with a CD30 antibody |
MY148086A (en) | 2005-04-29 | 2013-02-28 | Rinat Neuroscience Corp | Antibodies directed against amyloid-beta peptide and methods using same |
WO2006119449A2 (fr) | 2005-05-04 | 2006-11-09 | Vectorlogics, Inc. | Adenovirus modifie contenant un anticorps stabilise |
EP1879613B1 (fr) | 2005-05-05 | 2011-11-30 | Merck Sharp & Dohme Corp. | Compositions à base de conjugués peptidiques et méthodes destinées à la prévention et au traitement de la maladie d'alzheimer |
ATE530667T1 (de) | 2005-05-27 | 2011-11-15 | Evotec Neurosciences Gmbh | Kcnn3 als diagnostisches und therapeutisches target für alzheimer-krankheit |
US20060272038A1 (en) | 2005-05-27 | 2006-11-30 | Michael De Vivo | Transgenic Alzheimer's mouse model vectors and uses thereof |
CA2610771A1 (fr) | 2005-06-06 | 2006-12-14 | Wyeth | Anticorps monoclonaux anti-trkb et utilisations de ceux-ci |
EP1896504B1 (fr) | 2005-06-17 | 2012-11-21 | Wyeth LLC | Procedes de purification des anticorps contenant la region fc |
US7741448B2 (en) | 2005-06-21 | 2010-06-22 | Medical & Biological Laboratories Co., Ltd. | Antibody having inhibitory effect on amyloid fibril formation |
TW200726482A (en) | 2005-06-30 | 2007-07-16 | Merck & Co Inc | Method for preparing a covalently cross linked oligomer of amyloid beta peptides |
TW200726774A (en) | 2005-06-30 | 2007-07-16 | Merck & Co Inc | Composition and method for producing stable amyloid beta oligomers |
RS53058B (en) | 2005-07-08 | 2014-04-30 | Biogen Idec Ma Inc. | SP35 ANTIBODIES AND THEIR APPLICATIONS |
JP5102205B2 (ja) | 2005-07-13 | 2012-12-19 | コイミュン インコーポレイテッド | 触媒免疫グロブリン |
WO2007011834A2 (fr) | 2005-07-15 | 2007-01-25 | The Regents Of The University Of California | Composes et procede pour diagnostiquer et traiter les maladies associees aux amyloides |
CA2618508A1 (fr) | 2005-08-10 | 2007-02-22 | Oklahoma Medical Research Foundation | Compositions de memapsine 2 tronquee et traitements associes |
GB2429013C (en) | 2005-08-11 | 2012-11-28 | Arpi Matossian-Rogers | Peptides for treatment and diagnosis of autoimmunedisease |
KR20080068004A (ko) | 2005-08-15 | 2008-07-22 | 아라나 테라퓨틱스 리미티드 | 뉴 월드 영장류 구조형성영역을 가진 조작 항체 |
US8124076B2 (en) | 2005-08-18 | 2012-02-28 | Ramot At Tel Aviv University Ltd. | Single chain antibodies against β-amyloid peptide |
US7612181B2 (en) | 2005-08-19 | 2009-11-03 | Abbott Laboratories | Dual variable domain immunoglobulin and uses thereof |
JP2007077103A (ja) | 2005-09-16 | 2007-03-29 | Yokohama City Univ | アルツハイマー病の予防又は治療剤 |
EP1934341A1 (fr) | 2005-10-03 | 2008-06-25 | AstraZeneca AB | Proteines de fusion ayant une demi-vie modulee dans du plasma |
CA2625440C (fr) | 2005-10-11 | 2023-06-13 | Micromet Ag | Compositions comportant des anticorps specifiques d'especes croisees et leurs utilisations |
EP1940466B1 (fr) | 2005-10-21 | 2012-11-28 | Merck Sharp & Dohme Corp. | Anticorps monoclonaux anti-addl et leur utilisation |
US20070092508A1 (en) | 2005-10-21 | 2007-04-26 | Recombiant Technologies, Llc | Detoxification depot for Alzheimer's disease |
AU2006304804B2 (en) | 2005-10-21 | 2011-06-02 | Vertex Pharmaceuticals Incorporated | Modified proteases that inhibit complement activation |
US20090202531A1 (en) | 2005-11-01 | 2009-08-13 | Novartis Ag | Uses of anti-cd40 antibodies |
US20090181008A1 (en) | 2005-11-10 | 2009-07-16 | Satoris, Inc. | Methods of treating alzheimer's disease |
US8316104B2 (en) | 2005-11-15 | 2012-11-20 | California Institute Of Technology | Method and apparatus for collaborative system |
US20080014596A1 (en) | 2005-11-16 | 2008-01-17 | Jasna Jerecic | ADDL Binding to Hippocampal Neurons |
US9133267B2 (en) | 2005-11-22 | 2015-09-15 | The Trustees Of The University Of Pennsylvania | Antibody treatment of Alzheimer's and related diseases |
JP2009518010A (ja) | 2005-11-30 | 2009-05-07 | アボット・ラボラトリーズ | ヒトβアミロイドタンパク質の組み換え形態の調製方法及びこれらのタンパク質の使用 |
CN102898519B (zh) | 2005-11-30 | 2015-10-28 | Abbvie公司 | 抗淀粉样β蛋白的单克隆抗体及其用途 |
PL2289909T3 (pl) | 2005-11-30 | 2015-04-30 | Abbvie Inc | Sposób przeszukiwania, proces oczyszczania niedyfundujących oligomerów Abeta, selektywne przeciwciała przeciw niedyfundującym oligomerom Abeta i sposób wytwarzania tych przeciwciał |
US20070237764A1 (en) | 2005-12-02 | 2007-10-11 | Genentech, Inc. | Binding polypeptides with restricted diversity sequences |
WO2007067512A2 (fr) | 2005-12-08 | 2007-06-14 | Merck & Co., Inc. | Procede pour identifier des modulateurs d'adprh convenant pour traiter la maladie d'alzheimer |
RS52004B (en) | 2005-12-12 | 2012-04-30 | F. Hoffmann-La Roche Ag | ANTIBODIES AGAINST AMYLOID BETA WITH GLYCOSILATION IN THE VARIABLE REGION |
KR101505201B1 (ko) | 2005-12-12 | 2015-03-24 | 에이씨 이뮨 에스.에이. | 치료적 특성을 갖는 베타 1-42 특이적인 단일클론성 항체 |
AU2006326283B2 (en) | 2005-12-12 | 2012-01-19 | Ac Immune S.A. | Therapeutic vaccine |
JP5358187B2 (ja) | 2005-12-15 | 2013-12-04 | ジェネンテック, インコーポレイテッド | ポリユビキチンを標的とする方法と組成物 |
US20080058276A1 (en) | 2006-01-13 | 2008-03-06 | Cornell Research Foundation, Inc. | Alzheimer's disease therapeutics based on pin-1 catalyzed conformational changes in phosphorylated amyloid precursor protein |
EP1811304A1 (fr) | 2006-01-18 | 2007-07-25 | Friedrich-Alexander-Universität Erlangen-Nürnberg | Grandes particules de liaison de peptide Aß (LAPS) dans le diagnostic et la thérapie de la maladie d'Alzheimer |
CN1329413C (zh) | 2006-01-23 | 2007-08-01 | 南京医科大学 | 一种治疗或预防老年性痴呆的抗体及其表达载体和在制药中的应用 |
PT1981540E (pt) | 2006-01-30 | 2013-05-07 | Grifols Therapeutics Inc | Método de tratamento e profilaxia de doenças relacionadas com a deposição de amilóides utilizando igm |
GB0601976D0 (en) | 2006-02-01 | 2006-03-15 | Merck Sharp & Dohme | Proteins |
US20090304712A1 (en) | 2006-02-02 | 2009-12-10 | National University Corporation Nagoya University | Neuronal Cell Death Inhibitor and Screening Method |
EP1984396A2 (fr) | 2006-02-06 | 2008-10-29 | Elan Pharmaceuticals Inc. | Inhibiteurs specifiques de la preseniline-i et leur utilisation |
JP2009526020A (ja) | 2006-02-09 | 2009-07-16 | ノバルティス アクチエンゲゼルシャフト | 分泌型frizzled関連タンパク質4(SFRP−4)タンパク質結合剤 |
CA2643048A1 (fr) | 2006-02-21 | 2007-08-30 | Oklahoma Medical Research Foundation | Traitement de la maladie d'alzheimer avec des inhibiteurs de la fixation de l'apoe au recepteur de l'apoe |
US20070196367A1 (en) | 2006-02-22 | 2007-08-23 | Valentin Dinu | Methods of preventing and treating Alzheimer's disease, age related macular degeneration and other diseases involving extra-cellular debris through the inhibition of the complement system |
WO2007097251A1 (fr) | 2006-02-22 | 2007-08-30 | Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo | VACCIN PEPTIDIQUE DESTINE A INDUIRE LA PRODUCTION D'ANTICORPS ANTI-PEPTIDE AMYLOIDE β |
ZA200807228B (en) | 2006-02-24 | 2009-11-25 | Chiesi Farma Spa | Anti-amyloid immunogenic compositions, methods and uses |
US20100196932A1 (en) | 2006-03-02 | 2010-08-05 | The Board Of Trustees Of The University Of Illinois | Yeast Reporter System |
JP5823663B2 (ja) | 2006-03-03 | 2015-11-25 | プロミス ニューロサイエンシズ インコーポレイテッド | ミスフォールドsod1媒介疾患を処置および検出するための方法および組成物 |
WO2007109107A2 (fr) | 2006-03-17 | 2007-09-27 | The Trustees Of Columbia University In The City Of New York | Atf4 utilisé comme cible thérapeutique dans la maladie d'alzheimer et autres troubles neurologiques |
BRPI0708970A2 (pt) | 2006-03-21 | 2011-06-21 | Wyeth Corp | método para o tratamento de um sujeito com uma doença ou transtorno caracterizado por depósito amilóide de a-beta; método de inibição ou redução da acumulação de depósito amilóide de a-beta em um sujeito; método de inibição ou redução da neurodegeneração em um sujeito; e método de inibição ou redução do declìnio cognitivo, ou de melhora da cognição, em um sujeito |
WO2007112288A2 (fr) | 2006-03-23 | 2007-10-04 | Mount Sinai School Of Medicine | Composition cardiovasculaire et utilisation de ladite composition pour le traitement de la maladie d'alzheimer |
EP2325209A3 (fr) | 2006-03-23 | 2011-08-03 | BioArtic Neuroscience AB | Anticorps améliorés sélectifs de protofibrilles et leur utilisation |
CA2541522A1 (fr) | 2006-03-28 | 2007-09-28 | E. Rick Preddie | Dosage immunoenzymatique double pour detecter la maladie de l'alzheimer avec applications pour des vaccins therapeutiques visant a enrayer la maladie |
PL2177536T3 (pl) | 2006-03-30 | 2014-11-28 | Glaxo Group Ltd | Przeciwciała przeciwko peptydowi beta-amyloidu |
FR2899107B1 (fr) | 2006-03-30 | 2008-06-13 | Neurokin Entpr Unipersonnelle | Utilisation de la (s)-roscovitine pour la fabrication d'un medicament |
WO2007123680A2 (fr) | 2006-03-31 | 2007-11-01 | The Regents Of The University Of California | Procédés et compositions pour traiter des maladies neurodégénératives, en particulier la maladie d'alzheimer, et améliorer la mémoire normale |
JP4790013B2 (ja) | 2006-04-13 | 2011-10-12 | エーディア株式会社 | β−アミロイドの血中分解速度測定によるアルツハイマー病の検定に用いられる方法及び診断試薬 |
CN101058608B (zh) | 2006-04-21 | 2011-02-23 | 杜如昱 | 人类抗Aβ1-32淀粉样蛋白抗体、其纯化方法及用途 |
CA2649359A1 (fr) | 2006-04-21 | 2007-11-01 | Peoplebio, Inc. | Procede de detection differentielle d'une forme multimere et d'une forme monomere dans des polypeptides formant des multimeres par interactions tridimensionnelles |
JP5311303B2 (ja) | 2006-04-25 | 2013-10-09 | 国立大学法人 東京大学 | アルツハイマー病および癌の治療薬 |
CA2650376A1 (fr) | 2006-04-27 | 2007-11-08 | The Mclean Hospital Corporation | Methodes de traitement et de criblage servant a promouvoir la neurogenese |
GB0608386D0 (en) | 2006-04-27 | 2006-06-07 | Senexis Ltd | Compounds |
CA2650704A1 (fr) | 2006-04-28 | 2007-11-08 | Northwestern University | Sels de composes de pyridazine |
JP2007300856A (ja) | 2006-05-11 | 2007-11-22 | Hiroshi Mori | アミロイドタンパク質模倣物 |
US20070292895A1 (en) | 2006-05-19 | 2007-12-20 | Xiao-Ping Shi | Assays and methods to detect beta-secretase and its activity in body fluids and tissue extracts |
JP2009538924A (ja) | 2006-06-01 | 2009-11-12 | エラン ファーマシューティカルズ,インコーポレイテッド | Appの神経活性断片 |
US7427342B2 (en) | 2006-06-02 | 2008-09-23 | General Electric Company | Method and apparatus for shifting current distribution in electrodeionization systems |
JP4933159B2 (ja) | 2006-06-02 | 2012-05-16 | 国立大学法人金沢大学 | アルツハイマー病の診断方法 |
US7479550B2 (en) | 2006-06-02 | 2009-01-20 | The Board Of Regents Of The University Of Texas System | Amyloid β gene vaccines |
WO2007144198A2 (fr) | 2006-06-16 | 2007-12-21 | Umc Utrecht Holding B.V. | INHIBITEURS DU FPLR-1 (FLIPr ET TYPE FLIPr) À UTILISER DANS DES MALADIES IMPLIQUANT DES ÉPISODES INFLAMMATOIRES INDUITS PAR LES AMYLOÏDES ET DES MALADIES MÉDIÉES PAR LE COMPLEXE IMMUNITAIRE |
TW200815469A (en) | 2006-06-23 | 2008-04-01 | Astrazeneca Ab | Compounds |
WO2008002893A2 (fr) | 2006-06-29 | 2008-01-03 | Centocor, Inc. | Anticorps anti-amyloïdes, compositions, procédés et utilisations |
US20080058330A1 (en) | 2006-07-06 | 2008-03-06 | Roskamp Research Llc | Compounds and Combinations Thereof for Inhibiting Beta-Amyloid Production and Methods of Use Thereof |
JP2009544158A (ja) | 2006-07-13 | 2009-12-10 | パーカー.ハニフィン.コーポレイション | 電磁障害吸収用填隙性材料 |
CL2007002070A1 (es) | 2006-07-14 | 2008-02-08 | Ac Immune S A Genentech Inc | Anticuerpo quimerico o humanizado, o fragmentos de ellos, que se adhieren especificamente a por lo menos un epitopo en la proteina beta-amiloide; molecula de acido nucleico que lo codifica; composicion que lo comprende; su uso para tratar enfermedade |
WO2008008463A2 (fr) | 2006-07-14 | 2008-01-17 | Trustees Of Columbia University In The City Of New York | PROCÉDÉS ET COMPOSITIONS SERVANT À DÉTECTER ET QUANTIFIER sAPPβ |
ATE426174T1 (de) | 2006-07-28 | 2009-04-15 | Vista Ventures Gmbh | Verfahren zum nachweis der amyloid-beta oligomere in kírperflussigkeiten |
US7705475B2 (en) | 2006-08-03 | 2010-04-27 | Stats Chippac Ltd. | Integrated circuit package system |
EP2047393A1 (fr) | 2006-08-04 | 2009-04-15 | Lonza Biologics plc. | Procédé permettant de prédire l'agrégation d'une protéine et de concevoir des inhibiteurs d'agrégation |
WO2008021296A2 (fr) | 2006-08-14 | 2008-02-21 | Thymon, L.L.C. | Compositions et méthodes pour le traitement et la prévention de la maladie d'alzheimer |
AU2007285763B2 (en) | 2006-08-18 | 2011-12-15 | Armagen Technologies, Inc. | Agents for blood-brain barrier delivery |
WO2008051326A2 (fr) | 2006-08-21 | 2008-05-02 | President And Fellows Of Harvard College | Identification de contactines et de cams l1 en tant que ligands pour la protéine précurseur amyloïde |
WO2008070229A2 (fr) | 2006-08-28 | 2008-06-12 | Case Western Reserve University | Détection d'agrégats pathogènes de protéine dans un échantillon par elisa homologue |
US8372399B2 (en) | 2006-08-31 | 2013-02-12 | Cardiac Pacemakers, Inc. | Bispecific antibodies and agents to enhance stem cell homing |
JP2010502623A (ja) | 2006-08-31 | 2010-01-28 | バイオジェン・アイデック・エムエイ・インコーポレイテッド | Nogoレセプターポリペプチドの末梢投与に関する方法 |
EP2074222A4 (fr) | 2006-09-06 | 2010-03-03 | Univ Texas | Méthodes et compositions pour la détection de troubles du repliement des protéines |
WO2008030251A1 (fr) | 2006-09-08 | 2008-03-13 | Georgetown University | Anticorps deglycosylés anti-bêta amyloïde |
CA2662723A1 (fr) | 2006-09-08 | 2008-03-13 | Vib Vzw | Moyens et procedes pour la production d'oligomeres amyloides |
ES2307396B1 (es) | 2006-09-14 | 2009-09-30 | Fundacion Para Investigaciones Neurologicas (Fin) | Sistemas de eliminacion de sustancias neurotoxicas causantes de enfermedades neurodegenerativas mediante su atrapamiento selectivo por inmunoafinidad en el liquido cefalo-raquideo circulante. |
US7375190B2 (en) | 2006-09-19 | 2008-05-20 | National Yang-Ming University | Recombinant protein and method of screening for agents that modulate polypeptide aggregation |
CN101611054B (zh) | 2006-10-02 | 2013-12-25 | Ac免疫有限公司 | 针对淀粉状蛋白β的人源化抗体 |
US9382327B2 (en) | 2006-10-10 | 2016-07-05 | Vaccinex, Inc. | Anti-CD20 antibodies and methods of use |
US20100104577A1 (en) | 2006-10-10 | 2010-04-29 | Golde Todd E | Methods and materials related to anti-a (beta) antibodies |
JP5153114B2 (ja) | 2006-10-12 | 2013-02-27 | 知宏 千葉 | 新規のアルツハイマー病検出方法 |
US20080113444A1 (en) | 2006-10-17 | 2008-05-15 | Pray Todd R | Method for detecting oligermization of soluble amyloid beta oligomers |
GB0620735D0 (en) | 2006-10-18 | 2006-11-29 | Ares Trading Sa | Proteins |
KR100883132B1 (ko) | 2006-10-24 | 2009-02-10 | 재단법인서울대학교산학협력재단 | 아밀로이드 형성 펩타이드 또는 단백질의 가용성 회합체에선택적으로 작용하는 절단제 |
WO2008057240A2 (fr) | 2006-10-27 | 2008-05-15 | Abbott Biotechnology Ltd. | Anticorps anti-htnfalpha cristallisés |
WO2008130449A2 (fr) | 2006-11-20 | 2008-10-30 | Satori Pharmaceuticals, Inc. | Modulateurs de la production de bêta-amyloïde |
WO2008064244A2 (fr) | 2006-11-20 | 2008-05-29 | The Trustees Of Columbia University In The City Of New York | Modulation des phosphoinositides pour le traitement de maladies neurodégénératives |
US20100183513A1 (en) | 2006-11-24 | 2010-07-22 | Wolfgang Froestl | N-(methyl) -1h-pyrazol-3-amine, n-(methyl)-pyridin-2-amine and n-(methyl)-thiazol-2-amine derivatives for the treatment of diseases associated with amyloid or amyloid-like proteins, like e.g. alzheimer's |
US8455626B2 (en) | 2006-11-30 | 2013-06-04 | Abbott Laboratories | Aβ conformer selective anti-aβ globulomer monoclonal antibodies |
WO2008143708A2 (fr) | 2006-12-07 | 2008-11-27 | Mayo Foundation For Medical Education And Research | Procédés et matériaux associés à des anticorps anti-amyloïdes |
EP2094729A1 (fr) | 2006-12-11 | 2009-09-02 | F.Hoffmann-La Roche Ag | Formulation parentérale d'anticorps anti-peptide abêta |
WO2008076262A2 (fr) | 2006-12-15 | 2008-06-26 | Merck & Co., Inc. | Récepteur pour bêta amyloïde et utilisations de celui-ci |
AU2008204335B2 (en) | 2007-01-11 | 2013-06-13 | Michael Bacher | Diagnosis and treatment of Alzheimer's and other neurodementing diseases |
WO2008140639A2 (fr) | 2007-02-08 | 2008-11-20 | Oligomerix, Inc. | Biomarqueurs et dosages pour la maladie d'alzheimer |
KR100806914B1 (ko) | 2007-02-14 | 2008-02-22 | 경북대학교 산학협력단 | 퇴행성 신경질환의 예방 및 치료를 위한 리포칼린 2의 신규한 용도 |
US20100311767A1 (en) | 2007-02-27 | 2010-12-09 | Abbott Gmbh & Co. Kg | Method for the treatment of amyloidoses |
EP2125015A1 (fr) | 2007-02-27 | 2009-12-02 | Abbott GmbH & Co. KG | Méthode de traitement d'amyloïdoses |
GB0704394D0 (en) | 2007-03-07 | 2007-04-11 | Senexis Ltd | Compounds |
US20090022728A1 (en) | 2007-03-09 | 2009-01-22 | Rinat Neuroscience Corporation | Methods of treating ophthalmic diseases |
EP1978035A1 (fr) | 2007-04-05 | 2008-10-08 | Hans-Knöll-Institut Leibniz-Institut für Naturstoff-Forschung | Anticorps anti-amyloïdes et leur utilisation dans le diagnostic et la thérapie des maladies amyloïdes |
EP2656839A1 (fr) | 2007-04-12 | 2013-10-30 | Waratah Pharmaceuticals, Inc. | Utilisation de dérivés de cyclohexanehexol dans le traitement de maladies oculaires |
KR20100016661A (ko) | 2007-04-18 | 2010-02-12 | 얀센 알츠하이머 이뮤노테라피 | 대뇌 아밀로이드 혈관병증의 예방 및 치료 |
CA2683053A1 (fr) | 2007-04-19 | 2008-10-30 | Vib Vzw | Compositions d'oligonucleotides pour le traitement de la maladie d' alzheimer |
US9217036B2 (en) | 2007-04-26 | 2015-12-22 | Yale University | Prion protein as a receptor for amyloid-β oligomers |
WO2008150467A1 (fr) | 2007-05-30 | 2008-12-11 | The Regents Of The University Of Michigan | Essais préliminaires pour des inhibiteurs du canal ionique de peptide bêta-amyloïde |
US20090232801A1 (en) | 2007-05-30 | 2009-09-17 | Abbot Laboratories | Humanized Antibodies Which Bind To AB (1-42) Globulomer And Uses Thereof |
US20090175847A1 (en) | 2007-05-30 | 2009-07-09 | Abbott Laboratories | Humanized antibodies to ab (20-42) globulomer and uses thereof |
EP2574345A1 (fr) | 2007-06-12 | 2013-04-03 | AC Immune S.A. | Anticorps humanisés à amyloïde bêta |
NZ601843A (en) | 2007-06-12 | 2014-01-31 | Ac Immune Sa | Monoclonal anti beta amyloid antibody |
EP2009445A1 (fr) | 2007-06-29 | 2008-12-31 | Institut Pasteur | Utilisation d'anticorps à domaine simple de chaînes pour détecter une formule oligomérique d'un peptide amyloide bêta et ses applications |
CN101084909A (zh) | 2007-07-03 | 2007-12-12 | 福建医科大学附属协和医院 | 人参皂苷Rg1的新用途 |
ES2401664T3 (es) | 2007-07-12 | 2013-04-23 | Acumen Pharmaceuticals, Inc. | Procedimientos de modificación de oligómeros beta amiloides utilizando compuestos no peptídicos |
WO2009008891A1 (fr) | 2007-07-12 | 2009-01-15 | Acumen Pharmaceuticals, Inc. | Procédés d'amélioration de la fonction cognitive en utilisant des composés non peptidiques |
EP2194975A2 (fr) | 2007-07-12 | 2010-06-16 | Acumen Pharmaceuticals, Inc. | PROCÉDÉS CONSISTANT À INHIBER LA FORMATION DE LIGANDS DIFFUSABLES D'AMYLOIDE-ß UTILISANT DES COMPOSÉS D'ACYLHYDRAZIDE |
US8962677B2 (en) | 2007-07-12 | 2015-02-24 | Acumen Pharmaceuticals, Inc. | Methods of restoring cognitive ability using non-peptidic compounds |
GB0719559D0 (en) | 2007-10-05 | 2007-11-14 | Senexis Ltd | Compounds |
EP2650308A3 (fr) | 2007-10-05 | 2014-11-12 | Genentech, Inc. | Utilisation d'anticorps anti-beta amyloide aux maladies oculaires |
WO2009048539A2 (fr) | 2007-10-05 | 2009-04-16 | Genentech, Inc. | Anticorps monoclonal |
BRPI0818621A8 (pt) | 2007-10-05 | 2018-01-30 | Ac Immune Sa | composição farmacêutica, e, métodos para reduzir a carga da placa e a quantidade de placas na camada de célula de gânglio retinal de um indivíduo, para prevenir, tratar e/ou aliviar os efeitos de uma doença ocular, para diagnosticar uma doença ocular e uma predisposição a uma doença ocular, para monitorar doença ocular, para predizer responsividade de um paciente, e para reter ou diminuir pressão ocular nos olhos de um indivíduo |
CN101152576A (zh) | 2007-10-15 | 2008-04-02 | 王延江 | 防治阿尔茨海默病的药物 |
WO2010011947A2 (fr) | 2008-07-25 | 2010-01-28 | Abbott Laboratories | Analogues du peptide ss-amyloïde, oligomères de celui-ci, procédés de préparation et compositions comprenant lesdits analogues ou oligomères, et leurs utilisations |
US20100173828A1 (en) | 2008-07-25 | 2010-07-08 | Abbott Gmbh & Co. Kg | Aß(X - 38 .. 43) oligomers, and processes, compositions, and uses thereof |
ES2665495T3 (es) | 2009-02-25 | 2018-04-26 | Academia Sinica | Anticuerpos anti-CemX capaces de unirse a mIgE humana sobre linfocitos B |
EP2558494B1 (fr) | 2010-04-15 | 2018-05-23 | AbbVie Inc. | Protéines de liaison à la bêta amyloïde |
US9062101B2 (en) | 2010-08-14 | 2015-06-23 | AbbVie Deutschland GmbH & Co. KG | Amyloid-beta binding proteins |
-
2003
- 2003-01-31 DE DE10303974A patent/DE10303974A1/de not_active Withdrawn
-
2004
- 2004-02-02 KR KR1020097000681A patent/KR20090019911A/ko active Search and Examination
- 2004-02-02 JP JP2006501701A patent/JP5150097B2/ja not_active Expired - Lifetime
- 2004-02-02 NZ NZ541453A patent/NZ541453A/en not_active IP Right Cessation
- 2004-02-02 CA CA2514582A patent/CA2514582C/fr not_active Expired - Lifetime
- 2004-02-02 EP EP10179281.0A patent/EP2336161B1/fr not_active Expired - Lifetime
- 2004-02-02 NZ NZ563779A patent/NZ563779A/en not_active IP Right Cessation
- 2004-02-02 ES ES04707201.2T patent/ES2567437T3/es not_active Expired - Lifetime
- 2004-02-02 AU AU2004207075A patent/AU2004207075B2/en not_active Expired
- 2004-02-02 CN CN201010003325.7A patent/CN101985036B/zh not_active Expired - Lifetime
- 2004-02-02 MX MXPA05007964A patent/MXPA05007964A/es active IP Right Grant
- 2004-02-02 EP EP04707201.2A patent/EP1594891B1/fr not_active Expired - Lifetime
- 2004-02-02 CA CA3000519A patent/CA3000519A1/fr not_active Abandoned
- 2004-02-02 BR BR0407084-4A patent/BRPI0407084A/pt not_active IP Right Cessation
- 2004-02-02 CN CN200480008812A patent/CN100595210C/zh not_active Expired - Lifetime
- 2004-02-02 US US10/543,841 patent/US7902328B2/en active Active
- 2004-02-02 KR KR1020057014117A patent/KR20050103483A/ko active IP Right Grant
- 2004-02-02 EP EP10179255A patent/EP2336160A3/fr not_active Withdrawn
- 2004-02-02 EP EP10179297A patent/EP2336159A3/fr not_active Withdrawn
- 2004-02-02 WO PCT/EP2004/000927 patent/WO2004067561A1/fr active Application Filing
- 2004-02-02 CN CN201010004774.3A patent/CN101830974B/zh not_active Expired - Lifetime
- 2004-02-02 KR KR1020127003623A patent/KR20120042959A/ko not_active Application Discontinuation
-
2005
- 2005-08-30 ZA ZA200506934A patent/ZA200506934B/xx unknown
-
2009
- 2009-02-26 IL IL197312A patent/IL197312A0/en unknown
- 2009-09-14 US US12/559,255 patent/US20100209346A1/en not_active Abandoned
-
2010
- 2010-02-02 JP JP2010021337A patent/JP5448890B2/ja not_active Expired - Lifetime
- 2010-04-29 IL IL205430A patent/IL205430A0/en unknown
- 2010-12-22 AU AU2010257323A patent/AU2010257323B8/en not_active Expired
-
2011
- 2011-05-19 IL IL212997A patent/IL212997A0/en unknown
- 2011-08-01 US US13/195,533 patent/US9176150B2/en not_active Expired - Lifetime
-
2012
- 2012-07-09 JP JP2012153998A patent/JP2012250981A/ja active Pending
-
2013
- 2013-10-03 JP JP2013207888A patent/JP2014005295A/ja active Pending
-
2015
- 2015-09-24 US US14/864,526 patent/US10464976B2/en not_active Expired - Lifetime
Patent Citations (50)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4399216A (en) | 1980-02-25 | 1983-08-16 | The Trustees Of Columbia University | Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials |
US4634665A (en) | 1980-02-25 | 1987-01-06 | The Trustees Of Columbia University In The City Of New York | Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials |
US5179017A (en) | 1980-02-25 | 1993-01-12 | The Trustees Of Columbia University In The City Of New York | Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials |
US4510245A (en) | 1982-11-18 | 1985-04-09 | Chiron Corporation | Adenovirus promoter system |
US4816397A (en) | 1983-03-25 | 1989-03-28 | Celltech, Limited | Multichain polypeptides or proteins and processes for their production |
US5168062A (en) | 1985-01-30 | 1992-12-01 | University Of Iowa Research Foundation | Transfer vectors and microorganisms containing human cytomegalovirus immediate-early promoter-regulatory DNA sequence |
US4968615A (en) | 1985-12-18 | 1990-11-06 | Ciba-Geigy Corporation | Deoxyribonucleic acid segment from a virus |
EP0436597A1 (fr) | 1988-09-02 | 1991-07-17 | Protein Eng Corp | Production et selection de proteines de liaison diversifiees de recombinaison. |
US5837500A (en) | 1988-09-02 | 1998-11-17 | Dyax, Corp. | Directed evolution of novel binding proteins |
US5571698A (en) | 1988-09-02 | 1996-11-05 | Protein Engineering Corporation | Directed evolution of novel binding proteins |
US5403484A (en) | 1988-09-02 | 1995-04-04 | Protein Engineering Corporation | Viruses expressing chimeric binding proteins |
US5223409A (en) | 1988-09-02 | 1993-06-29 | Protein Engineering Corp. | Directed evolution of novel binding proteins |
EP0368684A1 (fr) | 1988-11-11 | 1990-05-16 | Medical Research Council | Clonage de séquences d'immunoglobulines de domaines variables. |
US5939598A (en) | 1990-01-12 | 1999-08-17 | Abgenix, Inc. | Method of making transgenic mice lacking endogenous heavy chains |
US5580717A (en) | 1990-05-01 | 1996-12-03 | Affymax Technologies N.V. | Recombinant library screening methods |
US5427908A (en) | 1990-05-01 | 1995-06-27 | Affymax Technologies N.V. | Recombinant library screening methods |
WO1991017271A1 (fr) | 1990-05-01 | 1991-11-14 | Affymax Technologies N.V. | Procedes de triage de banques d'adn recombine |
EP0527839A1 (fr) | 1990-05-01 | 1993-02-24 | Affymax Technologies N.V. | Procedes de triage de banques d'adn recombinant |
EP0589877A1 (fr) | 1990-07-10 | 1994-04-06 | Cambridge Antibody Tech | Procede de production de chainon de paires a liaison specifique. |
WO1992020791A1 (fr) | 1990-07-10 | 1992-11-26 | Cambridge Antibody Technology Limited | Methode de production de chainons de paires de liaison specifique |
WO1992001047A1 (fr) | 1990-07-10 | 1992-01-23 | Cambridge Antibody Technology Limited | Procede de production de chainon de paires a liaison specifique |
US5969108A (en) | 1990-07-10 | 1999-10-19 | Medical Research Council | Methods for producing members of specific binding pairs |
WO1992002551A1 (fr) | 1990-08-02 | 1992-02-20 | B.R. Centre Limited | Procedes de production de proteines presentant une fonction souhaitee |
US5627052A (en) | 1990-08-02 | 1997-05-06 | B.R. Centre, Ltd. | Methods for the production of proteins with a desired function |
US5545806A (en) | 1990-08-29 | 1996-08-13 | Genpharm International, Inc. | Ransgenic non-human animals for producing heterologous antibodies |
US5625126A (en) | 1990-08-29 | 1997-04-29 | Genpharm International, Inc. | Transgenic non-human animals for producing heterologous antibodies |
US5569825A (en) | 1990-08-29 | 1996-10-29 | Genpharm International | Transgenic non-human animals capable of producing heterologous antibodies of various isotypes |
US5633425A (en) | 1990-08-29 | 1997-05-27 | Genpharm International, Inc. | Transgenic non-human animals capable of producing heterologous antibodies |
US5877397A (en) | 1990-08-29 | 1999-03-02 | Genpharm International Inc. | Transgenic non-human animals capable of producing heterologous antibodies of various isotypes |
US5661016A (en) | 1990-08-29 | 1997-08-26 | Genpharm International Inc. | Transgenic non-human animals capable of producing heterologous antibodies of various isotypes |
US5814318A (en) | 1990-08-29 | 1998-09-29 | Genpharm International Inc. | Transgenic non-human animals for producing heterologous antibodies |
US5770429A (en) | 1990-08-29 | 1998-06-23 | Genpharm International, Inc. | Transgenic non-human animals capable of producing heterologous antibodies |
WO1992009690A2 (fr) | 1990-12-03 | 1992-06-11 | Genentech, Inc. | Methode d'enrichissement pour des variantes de l'hormone de croissance avec des proprietes de liaison modifiees |
US5885793A (en) | 1991-12-02 | 1999-03-23 | Medical Research Council | Production of anti-self antibodies from antibody segment repertoires and displayed on phage |
WO1996033735A1 (fr) | 1995-04-27 | 1996-10-31 | Abgenix, Inc. | Anticorps humains derives d'une xenosouris immunisee |
WO1996034096A1 (fr) | 1995-04-28 | 1996-10-31 | Abgenix, Inc. | Anticorps humains derives de xeno-souris immunisees |
WO1997008320A1 (fr) | 1995-08-18 | 1997-03-06 | Morphosys Gesellschaft Für Proteinoptimierung Mbh | Banques de proteines/(poly)peptides |
WO1997029131A1 (fr) | 1996-02-09 | 1997-08-14 | Basf Aktiengesellschaft | ANTICORPS HUMAINS SE FIXANT AU FACTEUR NECROSANT DES TUMEURS DE TYPE $g(a) |
WO1998024893A2 (fr) | 1996-12-03 | 1998-06-11 | Abgenix, Inc. | MAMMIFERES TRANSGENIQUES POSSEDANT DES LOCI DE GENES D'IMMUNOGLOBULINE D'ORIGINE HUMAINE, DOTES DE REGIONS VH ET Vλ, ET ANTICORPS PRODUITS A PARTIR DE TELS MAMMIFERES |
WO1998031700A1 (fr) | 1997-01-21 | 1998-07-23 | The General Hospital Corporation | Selection de proteines a l'aide de fusions arn-proteine |
US6218506B1 (en) | 1997-02-05 | 2001-04-17 | Northwestern University | Amyloid β protein (globular assembly and uses thereof) |
WO1998047343A2 (fr) | 1997-04-04 | 1998-10-29 | Biosite Diagnostics, Inc. | Bibliotheques polyvalentes et polyclonales |
WO1998049286A2 (fr) | 1997-05-01 | 1998-11-05 | Board Of Regents, The University Of Texas System | Evolution orientee d'enzymes et d'anticorps |
WO1999036569A1 (fr) | 1998-01-20 | 1999-07-22 | The Board Of Trustees Of The University Of Illinois | Proteines pour la presentation de la surface d'une cellule de levure et leurs utilisations |
WO1999045962A1 (fr) | 1998-03-13 | 1999-09-16 | Genpharm International, Inc. | Animaux transgeniques capables de fabriquer des anticorps heterologues |
WO1999053049A1 (fr) | 1998-04-15 | 1999-10-21 | Abgenix, Inc. | Production d'anticorps humains par des epitopes et formation de profils d'expression genique |
WO2000056772A1 (fr) | 1999-03-25 | 2000-09-28 | Knoll Gmbh | Anticorps humains se liant a l'interleukine-12 humaine et procedes de production de ces derniers |
WO2001010900A2 (fr) | 1999-08-04 | 2001-02-15 | University Of Southern California | PROTEINE D'AMYLOIDE β (ENSEMBLE GLOBULAIRE ET SES UTILISATIONS) |
WO2003016467A2 (fr) | 2001-08-17 | 2003-02-27 | Eli Lilly And Company | Utilisation d'anticorps ayant une forte affinite pour le peptide a$g(b) dans le traitement de pathologies et de maladies liees a a$g(b) |
WO2003016466A2 (fr) | 2001-08-17 | 2003-02-27 | Eli Lilly And Company | Anticorps anti-$g(a)$g(b) |
Non-Patent Citations (99)
Title |
---|
ALBERT, S.E. ET AL., J. IMMUNOL., vol. 159, 1997, pages 1393 - 1403 |
ARAI, K. ET AL., J. IMMUNOL. METHODS, vol. 217, 1998, pages 79 - 85 |
ARISPE ET AL., PNAS, vol. 90, 1993, pages 567 |
AUSUBEL, F.M. ET AL.: "Current Protocols in Molecular Biology", 1989, GREENE PUBLISHING ASSOCIATES |
BABCOCK, J.S. ET AL., PROC. NATL. ACAD. SCI. USA, vol. 93, 1996, pages 7843 - 7848 |
BARBAS ET AL., PNAS, vol. 88, 1991, pages 7978 - 7982 |
BIRD ET AL., SCIENCE, vol. 242, 1988, pages 423 - 426 |
BOCHER, W.O. ET AL., IMMUNOLOGY, vol. 96, 1999, pages 634 - 641 |
BOMBIL, F. ET AL., IMMUNOBIOL., vol. 195, 1996, pages 360 - 375 |
BOSS, M.A.; WOOD, C. R., IMMUNOLOGY TODAY, vol. 6, 1985, pages 12 - 13 |
BROWN ET AL., J BIOL CHEM, vol. 255, 1980, pages 4980 - 83 |
BROWN ET AL., J. LMMUNOL, vol. 127, 1981, pages 539 - 46 |
C. MASTERS ET AL., PNAS, vol. 82, 1985, pages 4245 - 4249 |
C. RUSSO ET AL., NATURE, vol. 405, 2000, pages 531 - 532 |
C.A. MCLEAN ET AL., ANN. NEUROL., vol. 46, 1999, pages 860 - 866 |
C.L. MASTERS ET AL., PNAS, vol. 82, 1985, pages 4245 - 4249 |
CHAMAT, S. ET AL., J. INFECT. DISEASES, vol. 180, 1999, pages 268 - 277 |
CHOI ET AL., J. NEUROSCI., vol. 7, 1987, pages 357 - 368 |
CLARKSON ET AL., NATURE, vol. 352, 1991, pages 624 - 628 |
D.J. SELKOE, NEURON, vol. 32, 2001, pages 177 - 180 |
D.'SCHENK., NAT. REV. NEUROSCI., vol. 3, 2002, pages 824 - 828 |
D.W. DICKSON ET AL., NEUROBIOL. AGING, vol. 16, 1995, pages 285 - 298 |
E. A. LERNER, YALE J. BIOL. MED., vol. 54, 1981, pages 387 - 402 |
E.B. LEE ET AL., JBS, vol. 278, 2003, pages 4458 - 4466 |
EREN, R. ET AL., IMMUNOLOGY, vol. 93, 1998, pages 154 - 161 |
FISHWILD, D. M. ET AL., NATURE BIOTECHNOLOGY, vol. 14, 1996, pages 845 - 851 |
FUCHS ET AL., BIOLTECHNOLOGY, vol. 9, 1991, pages 1370 - 1372 |
G. GALFRE ET AL., NATURE, vol. 266, 1977, pages 550 - 52 |
GALLO, M.L. ET AL., EUR. J. IMMUNOL., vol. 30, 2000, pages 534 - 540 |
GARRAD ET AL., BIO/TECHNOLOGY, vol. 9, 1991, pages 1373 - 1377 |
GEFTER ET AL., SOMATIC CELL GENET. |
GOEDDEL: "Gene Expression Technology: Methods in Enzymology", 1990, ACADEMIC PRESS, pages: 185 |
GRAM ET AL., PNAS, vol. 89, 1992, pages 3576 - 3580 |
GREEN, L.L., J. IMMUNOL. METHODS, vol. 231, 1999, pages 11 - 23 |
GREEN, L.L.; JAKOBOVITS, A., J. EXP. MED., vol. 188, 1998, pages 483 - 495 |
GRIFFITHS ET AL., EMBO J, vol. 12, 1993, pages 725 - 734 |
HARDING, F.A.; LONBERG, N., ANN. N.Y. ACAD. SCI., vol. 764, 1995, pages 536 - 546 |
HARLOW, E., AND LANE, D.,: "Antibodies, A Laboratory Manual", 1988, COLD SPRING HARBOR LABORATORY, article "Antikorpern als Hilfsmittel in Labor und Klinik" |
HAWKINS ET AL., J MOL BIOL, vol. 226, 1992, pages 889 - 896 |
HAY ET AL., HUM ANTIBOD HYBRIDOMAS, vol. 3, 1992, pages 81 - 85 |
HEARD, C. ET AL., MOLEC. MED., vol. 5, 1999, pages 35 - 45 |
HERZ, U. ET AL., INT. ARCH. ALLERGY IMMUNOL., vol. 113, 1997, pages 150 - 152 |
HOLLIGER, P. ET AL., PROC. NATL. ACAD. SCI. USA, vol. 90, 1993, pages 6444 - 6448 |
HOOGENBOOM ET AL., NUC ACID RES, vol. 19, 1991, pages 4133 - 4137 |
HUSE ET AL., SCIENCE, vol. 246, 1989, pages 1275 - 1281 |
HUSTON ET AL., PROC. NATI. ACAD. SCI. USA, vol. 85, 1988, pages 5879 - 5883 |
HUSTON ET AL., PROC. NATL. ACAD. SCI. USA, vol. 85, 1988, pages 5879 - 5883 |
HUTCHINS, W.A. ET AL., HYBRIDOMA, vol. 18, 1999, pages 121 - 129 |
J. NÄSLUND ET AL., PNAS, vol. 91, 1994, pages 8378 - 8382 |
J.R. ROBINSON,: "Sustained und Controlled Release Drug Delivery Systems", 1978, MARCEL DEKKER, INC. |
JOHNNSON, B. ET AL., ANAL. BIOCHEM., vol. 198, 1991, pages 268 - 277 |
JOHNSSON, B. ET AL., J. MOL. RECOGNIT., vol. 8, 1995, pages 125 - 131 |
JÖNSSON, U. ET AL., ANN. BIOL. CLIN., vol. 51, 1993, pages 19 - 26 |
JÖNSSON, U. ET AL., BIOTECHNIQUES, vol. 11, 1991, pages 620 - 627 |
KABAT ET AL.: "Sequences of Proteins of lmmunological Interest, Fifth Edition,", 1991, NIH PUBLICATION NR. 91-3242 |
KABAT, E.A. ET AL.: "Sequences of Proteins of Immunologicallnterest, Fifth Edition,", 1991, NIH PUBLICATION NR. 91-3242 |
KABAT, E.A. ET AL.: "Sequences of Proteins of Immunologieallnterest, Fifth Edition,", 1991, NIH PUBLICATION NR: 91-3242 |
KABAT, E.A. ET AL.: "Sequences of Proteins of lmmunological Interest, Fifth Edition,", 1991, NIH PUBLICATION NR. 91-3242 |
KIPRIYANOV, S.M. ET AL., HUMAN ANTIBODIES UND HYBRIDOMAS, vol. 6, 1995, pages 93 - 101 |
KIPRIYANOV, S.M. ET AL., MOL. IMMUNOL., vol. 31, 1994, pages 1047 - 1058 |
KNAPPIK ET AL., J. MOL. BIOL., vol. 296, 2000, pages 57 - 86 |
KOHLER; MILSTEIN, NATURE, vol. 256, 1975, pages 495 - 497 |
L.F. LUE ET AL., AM. J. PATHOL., vol. 155, 1999, pages 853 - 862 |
LÄMMLI UK, NATURE, vol. 227, 1970, pages 680 - 685 |
LASHUEL ET AL., NATURE, vol. 418, 2002, pages 291 |
LEADER, K.A. ET AL., IMMUNOLOGY, vol. 76, 1992, pages 229 - 234 |
LERNER, YALE J. BIOL. MED. |
LLAN, E. ET AL., HEPATOLOGY, vol. 29, 1999, pages 553 - 562 |
LONBERG, N. ET AL., NATURE, vol. 368, 1994, pages 856 - 859 |
LONBERG, N.; HUSZAR, D., INT. REV. IMMUNOL., vol. 13, 1995, pages 65 - 93 |
LUNN, M.P. ET AL., J. NEUROCHEM., vol. 75, 2000, pages 404 - 412 |
M. L. GEFTER ET AL., SOMATIC CELL GENET., vol. 3, 1977, pages 231 - 36 |
M.P. LAMBERT ET AL., J. NEUROCHEM., vol. 79, 2001, pages 595 - 605 |
M.P. LAMBERT ET AL., PNAS, vol. 95, 1998, pages 6448 - 6453 |
MACQUITTY, J.J.; KAY, R.M., SCIENCE, vol. 257, 1992, pages 1188 |
MCCAFFERTY ET AL., NATURE, vol. 348, 1990, pages 552 - 554 |
MENDEZ, M. J. ET AL., NATURE GENETICS, vol. 15, 1997, pages 146 - 156 |
MURPHY, W.J. ET AL., CLIN. IMMUNOL., vol. 90, 1999, pages 22 - 27 |
MURPHY, W.J. ET AL., SEMIN. IMMUNOL., vol. 8, 1996, pages 233 - 241 |
N. SERGEANT ET AL., J. OF NEUROCHEMISTRY, vol. 85, 2003, pages 1581 - 1591 |
NGUYEN, H. ET AL., MICROBIOL. IMMUNOL., vol. 41, 1997, pages 901 - 907 |
POLJAK, R.J. ET AL., STRUCTURE, vol. 2, 1994, pages 1121 - 1123 |
R. H. KENNETH: "Monoclonal Antibodies: A New Dimension In Biological Analyses", 1980, PLENUM PUBLISHING CORP. |
R.D.TERRY ET AL., ANN.NEUROL. 30., 1991, pages 572 - 580 |
R.J. KAUFMAN; P.A. SHARP, MOL. BIOL., vol. 159, 1982, pages 601 - 621 |
REISNER, Y; DAGAN, S., TRENDS BIOTECHNOL., vol. 16, 1998, pages 242 - 246 |
ROBERTS, R.W.; SZOSTAK, J.W., PROC. NATL. ACAD. SCI. USA, vol. 94, 1997, pages 12297 - 12302 |
ROES, J. ET AL., J. IMMUNOL. METHOD, vol. 183, 1995, pages 231 - 237 |
SAMBROOK, FRITSCH UND MANIATIS: "Molecular Cloning; A Laboratory Manual, Second Edition,", 1989, COLD SPRING HARBOR |
SMITHSON, S.L. ET AL., MOL. IMMUNOL., vol. 36, 1999, pages 113 - 124 |
T.C. SAIDO ET AL., NEURON, vol. 14, 1995, pages 457 - 466 |
TAYLOR, L.D. ET AL., NUCL. ACIDS RES., vol. 20, 1992, pages 6287 - 6295 |
TAYLOR, L.D. ET AL., NUCLEIC ACIDS RES., vol. 20, 1992, pages 6287 - 6295 |
URLAUB; CHASIN, PROC. NATL. ACAD. SCI. USA, vol. 77, 1980, pages 4216 - 4220 |
WARD ET AL., NATURE, vol. 341, 1989, pages 544 - 546 |
YANG, X.D. ET AL., J. LEUKOC. BIOL., vol. 66, 1999, pages 401 - 410 |
YEH ET AL., INT. J. CANCER, vol. 29, 1982, pages 269 - 75 |
YEH ET AL., PNAS, vol. 76, 1976, pages 2927 - 31 |
YOSHINARI, K.; ARAI, K., HYBRIDOMA, vol. 17, 1998, pages 41 - 45 |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP2336161B1 (fr) | Oligomères de beta(1-42 amyloïdes, dérivés de ceux-ci et anticorps destinés à ceux-ci, procédé de fabrication et utilisation de ces composés | |
DE60226036T3 (de) | ANTIKÖRPER, DER DAS GM1-GANGLIOSID-GEBUNDENE AMYLOID-b-PROTEIN ERKENNT, UND DNA, DIE FÜR DIESEN ANTIKÖRPER CODIERT | |
US9540432B2 (en) | Anti-Aβ globulomer 7C6 antibodies | |
DK2289909T3 (en) | The screening method, method of purification of non-diffusing alpha-beta oligomers selective antibodies to said non-diffunderingsdygtige alpha-beta oligomers and a method of producing said antibodies | |
DE102005002353A1 (de) | AGER-Rezeptor Multimerisierungs Epitope | |
DE102005015832A1 (de) | AGER-Rezeptor Multimerisierungs Epitope |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
AC | Divisional application: reference to earlier application |
Ref document number: 1594891 Country of ref document: EP Kind code of ref document: P |
|
AK | Designated contracting states |
Kind code of ref document: A2 Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PT RO SE SI SK TR |
|
AX | Request for extension of the european patent |
Extension state: LV |
|
PUAL | Search report despatched |
Free format text: ORIGINAL CODE: 0009013 |
|
AK | Designated contracting states |
Kind code of ref document: A3 Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PT RO SE SI SK TR |
|
AX | Request for extension of the european patent |
Extension state: LV |
|
RIC1 | Information provided on ipc code assigned before grant |
Ipc: C07K 14/47 20060101AFI20120201BHEP Ipc: G01N 33/68 20060101ALI20120201BHEP Ipc: C07K 16/18 20060101ALI20120201BHEP |
|
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1161881 Country of ref document: HK |
|
17P | Request for examination filed |
Effective date: 20120907 |
|
RAP1 | Party data changed (applicant data changed or rights of an application transferred) |
Owner name: ABBVIE DEUTSCHLAND GMBH & CO KG |
|
17Q | First examination report despatched |
Effective date: 20140721 |
|
RIC1 | Information provided on ipc code assigned before grant |
Ipc: G01N 33/68 20060101ALI20160712BHEP Ipc: C07K 16/18 20060101ALI20160712BHEP Ipc: A61K 39/00 20060101ALI20160712BHEP Ipc: C07K 14/47 20060101AFI20160712BHEP Ipc: A61K 38/17 20060101ALI20160712BHEP |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: EXAMINATION IS IN PROGRESS |
|
GRAP | Despatch of communication of intention to grant a patent |
Free format text: ORIGINAL CODE: EPIDOSNIGR1 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: GRANT OF PATENT IS INTENDED |
|
INTG | Intention to grant announced |
Effective date: 20170531 |
|
GRAS | Grant fee paid |
Free format text: ORIGINAL CODE: EPIDOSNIGR3 |
|
GRAA | (expected) grant |
Free format text: ORIGINAL CODE: 0009210 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE PATENT HAS BEEN GRANTED |
|
AC | Divisional application: reference to earlier application |
Ref document number: 1594891 Country of ref document: EP Kind code of ref document: P |
|
AK | Designated contracting states |
Kind code of ref document: B1 Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PT RO SE SI SK TR |
|
AX | Request for extension of the european patent |
Extension state: LV |
|
REG | Reference to a national code |
Ref country code: GB Ref legal event code: FG4D Free format text: NOT ENGLISH |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: EP |
|
REG | Reference to a national code |
Ref country code: AT Ref legal event code: REF Ref document number: 958199 Country of ref document: AT Kind code of ref document: T Effective date: 20180115 |
|
REG | Reference to a national code |
Ref country code: IE Ref legal event code: FG4D Free format text: LANGUAGE OF EP DOCUMENT: GERMAN |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R096 Ref document number: 502004015627 Country of ref document: DE |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: PLFP Year of fee payment: 15 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: FI Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20171227 |
|
REG | Reference to a national code |
Ref country code: NL Ref legal event code: MP Effective date: 20171227 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: GR Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20180328 Ref country code: BG Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20180327 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: NL Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20171227 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: SK Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20171227 Ref country code: EE Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20171227 Ref country code: CY Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20171227 Ref country code: CZ Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20171227 Ref country code: ES Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20171227 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: IT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20171227 Ref country code: RO Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20171227 |
|
REG | Reference to a national code |
Ref country code: HK Ref legal event code: WD Ref document number: 1161881 Country of ref document: HK |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: PL |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: MC Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20171227 |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R097 Ref document number: 502004015627 Country of ref document: DE |
|
PLBE | No opposition filed within time limit |
Free format text: ORIGINAL CODE: 0009261 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT |
|
REG | Reference to a national code |
Ref country code: IE Ref legal event code: MM4A |
|
REG | Reference to a national code |
Ref country code: BE Ref legal event code: MM Effective date: 20180228 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: CH Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20180228 Ref country code: DK Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20171227 Ref country code: LU Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20180202 Ref country code: LI Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20180228 |
|
26N | No opposition filed |
Effective date: 20180928 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: IE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20180202 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: BE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20180228 Ref country code: SI Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20171227 |
|
REG | Reference to a national code |
Ref country code: AT Ref legal event code: MM01 Ref document number: 958199 Country of ref document: AT Kind code of ref document: T Effective date: 20180202 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: AT Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20180202 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: TR Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20171227 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: PT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20171227 Ref country code: HU Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT; INVALID AB INITIO Effective date: 20040202 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: SE Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20171227 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: FR Payment date: 20230109 Year of fee payment: 20 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: GB Payment date: 20230111 Year of fee payment: 20 Ref country code: DE Payment date: 20230111 Year of fee payment: 20 |
|
P01 | Opt-out of the competence of the unified patent court (upc) registered |
Effective date: 20230331 |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R071 Ref document number: 502004015627 Country of ref document: DE |
|
REG | Reference to a national code |
Ref country code: GB Ref legal event code: PE20 Expiry date: 20240201 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: GB Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION Effective date: 20240201 |